Systems, methods and kits for peripheral nerve stimulation

ABSTRACT

Nerve stimulation systems and methods are disclosed for providing modulation of nerve targets in the lower limbs typically at or below the knee. For example, transcutaneous electrical nerve stimulation (TENS), percutaneous nerve stimulation, and implantable stimulation systems and methods are disclosed for providing stimulation to the saphenous nerve (SAFN). Additionally, systems and methods are provided for co-stimulating the posterior tibial nerve (PTN) and SAFN in combination with unique stimulation, and with control and display of OAB therapy protocols for multiple sites. Systems and methods of treatment can provide for management of usage and compliance monitoring, obtain and operating upon patient input responses to queries and management of payments and permissions related to provision of therapies for various disorders. Monitoring of usage and compliance can be managed both locally and remotely from a user. Stimulation provided in combination with a passive implantable component is also disclosed.

REFERENCE TO RELATED APPLICATIONS

This Patent Application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/375,898 filed 16 Aug. 2016 and is acontinuation-in-part of patent application Ser. No. 15/439,415, filed 22Feb. 2017, currently pending, which is a continuation of Ser. No.15/160,468, now U.S. Pat. No. 9,610,422, which claims the benefit ofU.S. Provisional Patent Application Ser. No. 62/171,549 filed 5 Jun.2015, expired, and Ser. No. 62/165,037 filed 21 May 2015, expired; andis a continuation-in-part of U.S. patent application Ser. No.14/553,427, filed Nov. 25, 2014 entitled Systems and Methods ofEnhancing Electrical Activation of Nervous Tissue which is based upon ofProvisional Patent Application Ser. No. 61/909,679, filed 27 Nov. 2013,expired; Provisional Patent Application Ser. No. 61/944,744, filed 26Feb. 2014, expired; and, Provisional Patent Application Ser. No.62/024,912, filed 15 Jul. 2014, expired.

INCORPORATION BY REFERENCE

This Patent application hereby incorporates by reference, U.S. patentapplication Ser. Nos. 15/160,468 and 14/553,427, and U.S. PatentApplications Ser. Nos. 61/909,679, 61/944,744, 62/024,912, 62/165,037,62/171,549, and 62/375,898, which are hereby incorporated by referencein entirety for all purposes.

FIELD

The subject concept relates to the field of modulating biologicaltissue.

BACKGROUND

Nerve stimulation (neurostimulation) technology includes applicationssuch as electrical neuromodulation, functional electrical stimulation,and therapeutic electrical stimulation. Nerve stimulation is aneffective clinical tool used to treat various chronic medical disordersand conditions. Examples include (1) deep brain stimulation (DBS) fortreating Parkinson's disease and essential tremor, (2) spinal cordstimulation for treating pain and voiding disorders, and (3) peripheralnerve stimulation for treating pelvic floor disorders and dysfunctions(e.g., overactive bladder), pain, obstructive sleep apnea, headache,migraine, epilepsy, depression, hypertension, cardiac disorders, andother disorders and disease states. Peripheral nerves may include, forexample, the vagus nerve, occipital nerve, cranial nerves, spinalnerves, pudendal nerves, cutaneous nerves, and the sciatic and femoralnerves.

The peripheral nervous system provides a neural substrate that allowsnerve stimulation to treat various disorders. Long-term viability ofimplanted neurostimulators can be complicated by issues related torepeated mechanical movement (e.g., lead fracture and/or componentmigration). Transcutaneous electrical nerve stimulation (TENS) canprovide a more simple and non-invasive approach. However, selectivenerve activation by TENS may not be readily achieved due to, forexample, intervening tissue or distance between a nerve target and theskin surface. Accordingly, some therapies rely on percutaneousstimulation in order to stimulate a target nerve.

Advances in minimally-invasive nerve stimulation have been realizedclinically. Wireless implantable electrode probes have been developedfor achieving less invasive methods of selective nerve stimulation. TheBION (Advanced Bionics) is a glass or ceramic covered electrode that canbe percutaneously injected into a region of interest. It can beself-powered or passively charged by radio frequency (RF) pulses.Long-term use may be complicated by migration of the BION from itsoriginal implant location. This migration may cause both reducedtherapeutic effects and increased stimulation-evoked side effects due toactivation of other (non-target) tissue. Nerve stimulation systems(e.g., MicroTransponder Inc. SAINT™ System) which are smaller, lessexpensive, and/or less technically complicated than the BION may beadvantageous in treatment of some disorders. StimGuard has developedinjectable implantable neurostimulators, which use wireless power in theRF and/or microwave frequency rage and non-inductive antennas whichreceive electromagnetic energy radiated from a source located outside ofthe patient's body. Energous technology is developing wirelesstechnology that utilizes multiple antennae to provide improvedtransmission and harvesting of wireless energy and is developing withinthe implantable device space. These innovative technologies will allowsmaller form factors. Witricity is using wireless magnetic inductiontechnology to power implanted devices. Alternatively, ValenciaTechnologies has developed a coin-shaped implantable neurostimulatordisclosed, for example in US App Nos. 20140214128A1, US20140214144A1,US20150148864A1, (all to Peterson et al.), which has a battery which maynot be rechargeable, and which can last 2-3 years when providingperiodic stimulation for disorders such as overactive bladder.

Transcutaneous magnetic stimulators (TMS), termed “transcranial magneticstimulators” when used for brain stimulation, are used to treatdisorders such as migraine (e.g. those made by Neuralieve Inc. such asU.S. Pat. Nos. 7,294,101, 8,262,556) by using an external magneticstimulation device to stimulate central or peripheral tissue targets.The fields induced inside the tissue by one or more pulses (e.g., suchas may occur with pulsed electromagnetic stimulation) may be lesslocalized than desired. The present invention may offer advantagesrelated to enhancing the effects of externally applied magnetic and/orelectrical fields near a target nerve.

In addition to pain treatment, TENS systems have been used to applyelectrical fields to the brain in order to modulate sleep, anxiety,depression, pain, attention, memory, and various types of brainactivity. Tens systems are being developed to enhance performance ofathletes by stimulating a person's head, although the mechanisms ofaction are not fully understood. TENS is not currently used to reliablytreat certain disorders such as overactive bladder. This may be due, atleast partially, to the difficulty of modulating the posterior tibialnerve which is typically too deep for the TENS signal to reliably reach.The disclosed systems and methods may allow a TENS system to stimulatenovel anatomical areas and nerve targets in the treatment of overactivebladder.

The first largely available percutaneous nerve stimulation method andsystem for treatment of overactive bladder was provided by Uroplastyunder the name “Urgent PC”. The therapy involves posterior tibial nervestimulation using a percutaneous needle electrode at a site above andposterior to the patient's medial malleolus which stimulates inconjunction with an electrode attached to the medial side of a patient'sfoot. The method and system has been described in U.S. Pat. Nos.6,493,588, 7,668,598, 8,046,082, 8,812,114, 9,056,194, 9,265,941assigned to Uroplasty. The Urgent PC system design incorporates a “use”status when the device is ready to provide therapy and a “do not use”status when the device is not ready. The device works with a lead sethaving a status flag element with a “use” status which converts to a “donot use” status at a predetermined time after start the therapy. Thestatus change includes blowing a fuse of the lead set so that the leadcannot be re-used for subsequent therapy. Single-use leads require a newlead must be purchased and used for each subsequent provision oftherapy.

A more recent alternative percutaneous nerve stimulation method andsystem has been described in U.S. Pat. Nos. 8,660,646 entitled“Percutaneous tibial nerve stimulator” to Laing et al. The disclosuredescribes a system developed by Advanced Uro-Solutions and nowdistributed under the name NURO by Medtronic. The system uses a methodthat includes providing a computer system having a customer interfaceand a neurostimulator unit that is operated in conjunction with theinterface. The neurostimulator has a pulse generator that iselectrically coupled to a transcutaneous electrode configured to beapplied to skin of a patient (e.g. inner foot) and a percutaneouselectrode for insertion at stimulation site of a patient which is theposterior tibial nerve. A microcontroller communicates with the pulsegenerator and allows for the monitoring of how many treatment creditsare available to be used by the neurostimulator. If there is at leastone treatment credit, the microcontroller allows for activating thepulse generator and decrements the treatment credit counter when atreatment is provided to a patient. The system also provides for acomputer system that can receive a treatment credit request transmittedthrough the customer interface and adjusting the number of treatmentcredits available based on the number of treatment credits purchased.Accordingly, the system allows for treatment to be accomplished as longas the treatment has been paid for by obtaining a treatment-creditbeforehand.

These prior art systems suffer a number of limitations. These provide asingle stimulator (e.g., configured to provide a single percutaneouselectrode for insertion at a single treatment site near the ankle). Morethan one stimulation site may be beneficial and stimulating thesaphenous nerve near the knee may have advantages. Stimulation systemsmay not allow for providing more than one treatment across a period oftime (e.g., 3- or 24-hours) although all treatments may be related to asingle event or disorder, but with greater severity, requiring a larger“dose”. For example, treatment credits are related to a singlestimulation session lasting a particular duration.

The prior art percutaneous stimulation devices for treatment of OAB bystimulation of the poster tibial nerve (PTN) suffer a number ofadditional disadvantages and limitations. For example, they are designedfor percutaneous stimulation of the PTN rather than for PTN or TENS ofthe saphenous nerve, or for a combination (e.g. first percutaneous andthen TENS). The SAFN which may be more sensitive to, and offer anadditional mechanism for, stimulation intended to modulate bladderactivity.

Another disadvantage is that prior art stimulators are not configured toadjust stimulation parameters for, and then provide stimulation with,signals provided at two or more percutaneous stimulators that areapplied to the patient to provide stimulation of targets including, forexample, both the PTN and the SAFN. There is no provision for display ofdifferent stimulation parameters related to two or more targets.

Another disadvantage is that prior art stimulators (e.g. percutaneous,magnetic, etc) used for treatment various conditions implement apay-per-session paradigm. For example, in the treatment of OAB (ormigraine) there is a charge to stimulate at a single stimulation site.This does not allow for stimulating using 1 or more neurostimulators orneedles at two stimulation sites. This also does not allow for requiringpayment to activate a device for a single interval of use rather thanfor a plurality of uses within that interval (e.g. several therapysessions on a particular day).

Another disadvantage is that prior art TENS stimulators (which workeither jointly, with or without, implanted components) are notconfigured to provide treatment related to overactive bladder withfeatures that promote compliance and therapy benefit. Prior art TENSstimulators are also not configured to provide stimulation of thesaphenous nerve in the treatment of overactive bladder or other pelvicfloor disorder.

Systems and methods are needed which provide advantages for bothclinic-based and home-based therapy such as one or more of thefollowing: a) providing at home stimulation treatment to patientscontingent upon a subscription being valid; b) allowing for providing aselected number of treatments within the course of a selected, andprogrammable, treatment window such as a 6, 12, 24 or 48 hour period, oran interval of weeks or months; c) monitoring, recording, displaying,reporting, sending and operating upon usage data related to treatmenttimes, durations, compliance, non-compliance, and other characteristicsof patient use; d) alerting doctors, caregivers, or patients to promotecompliance and/or when non-compliance or incorrect-use occurs; e)providing the selection of session-based, dose-based, interval-based,local-based and remote-based use-management; and, f) providing TENSsystems configured for OAB treatment and/or stimulation of the saphenousnerve to provide treatment of other disorders or provide other benefit.

SUMMARY

In an embodiment, a transcutaneous tissue stimulation system and methodis provided which includes one or more electrical generators positionedexternal to a patient. Stimulators which are either needle or TENSelectrodes are electrically coupled to the one or more electricalgenerators and are positioned on the surface of, or penetrate, thepatient's skin. Multiple target nerves may be defined with differentstimulation protocols as part of the treatment program.

In embodiments, systems and methods are provided for achieving effectivetherapeutic nerve activation of the SAFN with TENS of the medial portionof a patient's leg between approximately the knee and the medialmalleolus which can enable a primarily home-based TENS therapy treatmentfor OAB to become a simple and attractive (e.g. first-line) treatmentoption similar to lifestyle changes, or a second line treatment optionto be used rather than drug therapy, since this does not requireongoing, frequent clinic-visits for percutaneous intervention.

In embodiments, stimulation systems and methods are described forproviding advantages related to increasing therapeutic efficacy of nervestimulation, improving the comfort of a patient relative to alternativetherapeutic solutions, increasing patient compliance, decreasing thecost of treatment, and/or providing for a simple treatment usingexternal and/or implanted components.

In embodiments, an implanted, electrically conductive member ispositioned on, or contiguous to, a target nerve tissue for stimulationof the target nerve tissue to modify the electrical field signalsgenerated by the electrical generator and provided by the stimulator forthe purpose of modulating signals from the nerve tissue to the brain, tothe central or peripheral nervous system, or other target, of thepatient. System and methods aim to avoid activation of non-targetednervous tissue, which can both limit the overall therapeutic effects andexacerbate stimulation-evoked side effects. The implanted passiveelement is configured to allow therapy to achieve the same, or improvedtherapeutic benefit as that which would otherwise be achieved when usingonly transcutaneous nerve stimulation without an implanted passiveelement. The systems and methods for providing stimulation of tissueusing complementary or “paired” configurations of external stimulationelements and subcutaneously implanted passive elements.

Another objective is to provide systems and methods for achievingeffective therapeutic nerve activation with relatively lower stimulationamplitude and/or shorter pulse width than what is typically achievableusing prior art methods (e.g., TENS).

While the systems and methods disclosed herein are generally orientedfor peripheral stimulation, these may also be applied to stimulation ofother targets of the spine, brain, or body.

These and other objectives and advantages of the invention will now bedisclosed in the figures, detailed description, and claims of theinvention.

In the illustrated embodiments, any steps shown in the figures may occurin a different order, may be repeated, may lead to different steps ofthe method shown within each figure, or may lead to steps shown in otherfigures. Steps and components shown may be included or excluded from aparticular embodiment, and this may occur conditionally, or according tothe system or treatment protocol implemented by a therapy program. Thetherapy program may be implemented partially or fully by one or moreprocessors of a medical system which may include an external, or apartially or fully implantable neurostimulator. The therapy program canbe adjusted according to control by, or therapy plan implemented by, apatient, doctor, remote medical service, or caregiver.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a view of a neurostimulation system applied to a patient forstimulating the saphenous and posterior tibial nerve targets accordingto an embodiment of the invention;

FIG. 2 is a view of a neurostimulation system having two neurostimulatordevices applied to portions of separate legs of a patient according toan embodiment of the invention;

FIG. 3A is a view of a neurostimulation system having twoneurostimulator devices applied to two portions of a single leg of apatient according to an embodiment of the invention;

FIG. 3B is a view of a TENS electrode linking system for linking theTENS circuits of two neurostimulator devices according to an embodimentof the disclosure;

FIG. 4 is a view of a neurostimulation system applied to a leg of apatient for providing percutaneous stimulation according to anembodiment of the disclosure;

FIG. 5 is a view of a neurostimulation system applied to a leg of apatient for providing transcutaneous stimulation according to analternative embodiment of the disclosure;

FIG. 6A is a view of target locations for a neurostimulation systemapplied to a back of a patient for providing transcutaneous stimulationaccording to an alternative embodiment of the disclosure;

FIG. 6B Shaded anatomical plot of the sensation perceived during SAFNstimulation, showing that as the amplitude was increased from thresholdskin (Tskin) to threshold where discomfort was experienced (Tlimit), theevoked sensation spread across the entire medial aspect of the lowerleg, down to the ankle (N=15 subjects).

FIGS. 7A and 7B show two displays related to patient compliance that canbe provided by a compliance module of a neurostimulator system.

FIG. 8 is a schematic diagram of a neurostimulator system and functionalmodules which may be used to realize embodiments of the currentinvention including the provision of tissue stimulation.

FIG. 9 is a schematic block diagram of circuitry that supports thefunctional modules of an embodiment of a neurostimulator system.

FIGS. 10A and 10B are views of example displays that serve as userinterfaces in an embodiment of the system.

FIGS. 11A,B,C show alternative TENS accessories and embodiments for usewith the current invention.

FIG. 12 shows a flow chart of a method for providing therapy.

FIGS. 13A and 13B show additional flow charts of a method for providingtherapy.

FIG. 14 shows a TENS system having an electrode array and aneurostimulator.

FIG. 15 shows a top and bottom portion of a neurostimulator.

FIG. 16 plots the selectivity ratio (SR), which shows the relativeactivation of TN/SAFN by PTNS was strongly dependent on the depth andanterior-posterior position of the uninsulated (top row) and insulated(bottom row) needle.

FIG. 17 plots the percentage change in the selectivity ratio, whichquantifies the relative activation of the TN in comparison to eachindividual SAFN branch (A to E), that resulted when the uninsulatedneedle was replaced with an insulated needle electrode.

FIG. 18 plots the percentage of SAFN branches that are activated by PTNSsimulated at varying stimulation amplitudes. The results obtained withan uninsulated needle electrode (top row) are compared to those obtainedwith an insulated needle electrode

FIG. 19 plots the average electrode-to-nerve distance that achievesactivation of one or more SAFN branches. Simulations were conducted atmultiple stimulation amplitudes (0.5 T to 4 T).

FIG. 20 shows amplitude stimulation trials (10-minutes each) fordifferent frequencies, with 20 Hz resulting in the most significantreduction of average bladder contraction rate (BCR).

FIG. 21 plots the effectiveness of SAFN stimulation as percentage ofexperiments showing decreased BCR both during (intra) and after (post)stimulation.

FIG. 22 shows a screen related to querying patients about the number oftrips they made to the bathroom.

FIG. 23 shows a screen related to querying patients about the urgencyrelated to voiding.

FIG. 24 plots the percentage of experiments in which loss of bladderfunction was observed in response to SAFN stimulation (25 μA) applied atdifferent pulse frequencies (10 Hz and 20 Hz) and stimulus durations (10min, 20 min, and 40 min).

FIG. 25 plots prolonged changes in bladder function following SAFNstimulation (25 μA, 10 Hz, 40 minute duration) in anesthetized rats.

FIG. 26 shows a cross section of the human lower leg model that was usedto simulate PTN activation with surface TENS electrode.

FIG. 27 shows a lateral view of the lower leg model with an implantedpassive component (IPC) in the form of a nerve cuff.

FIG. 28 shows a cross section schematic of a patient's skin, a TENSelectrode, an IPC, and an underlying target nerve.

FIGS. 29A-C plot the change in neural excitability that is achieved witheTENS. This is expressed by the relative excitation, which wasdetermined by comparing either the activating function (AF) or the nerveactivation thresholds predicted by the MRG model. The effects of eTENSwas determined at multiple locations along the length of the nerve.

FIG. 30 shows the effects of the electrical conductivity of the IPC onthe relative excitation achieved by eTENS.

FIG. 31 shows the effects of the IPC length on the relative excitationachieved by eTENS.

FIG. 32 shows the change in the electrical potential along a single axonwithin the target nerve that is caused by the IPC. The conductive cuff(IPC) generates an isopotential region and also sharp potentialgradients at both edges of the IPC.

FIG. 33A compares the simulated radial current measured during TENS andeTENS, using the same monopolar surface electrode.

FIG. 33B, compares the simulated longitudinal current flowing throughthe endoneurium during TENS and eTENS.

FIG. 33C, shows changes in the simulated ratio of radial currents bothwith and without the presence of an electrode cuff that works inconjunction with a monopolar TENS electrode.

FIG. 33D, shows changes in the simulated ratio of axial currents bothwith and without the presence of an electrode cuff that works inconjunction with a monopolar TENS electrode.

FIG. 34A, shows changes in the simulated current density with thepresence of a nerve cuff that works in conjunction with a monopolar TENSelectrode, and demonstrates that the change in orientation of currentdensity is greatest at the proximal and distal tips of the passive nervecuff (represented in the figure with dotted rectangular pattern).

FIG. 34B, shows how the activating function changes as a position alongthe length of the nerve of the figure above and indicates that thepositive and negative AF at the edges of the cuff correspond to greatestdegree of nerve depolarization and hyperpolarization.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to exemplary embodiments of thepresent disclosure, examples of which are illustrated in theaccompanying drawings. Where possible, the same reference numbers willbe used throughout the drawings to refer to the same or like components.When titles are provided for different sections of this disclosure theseare merely to highlight certain themes and are not meant to limit theinvention concept.

FIG. 1 shows an embodiment of neuro stimulation system 10 applied to apatient for stimulating one or more targets in the leg of a patient 6which in this example are a saphenous nerve target and posterior tibialnerve target. The neurostimulator 50 has a housing 12 and a power button14 for turning the device on and off. A set of dedicated buttoncontrollers 16 (labeled 1, 2, and 3 in the figure) provide functionalitysuch as for starting stimulation (e.g. beginning a treatment sessionthat will last a selected time interval), pausing stimulation, andhalting stimulation. The “pause” function can allow the therapy to bepaused and restarted within a specified interval after the stimulationis started without blowing a fuse of the electrode lead set (Uroplastytype system) or decrementing the treatment credit (Nuro type system).This can allow for the needle to be repositioned if needed. A menucontroller 18 operating in conjunction with the user interface module 76allows a user to navigate through a set of menu options presented on thedisplay 20 to select and/or adjust operation of the system 10. Forexample, a user can adjust a therapy protocol parameter such as theamplitude of at least one stimulation signal that may be selectivelyprovided to one, two, or more stimulators such as a first and secondpercutaneous needle electrode 28 a, 28 b. The display 20 is configuredto present a user with information about stimulation parameter valuesrelated to stimulation of at least a first target (e.g. SAFN) and also asecond target (e.g. TN) when two or more stimulation targets aremodulated during therapy for overactive bladder or other disorder.

A conduit connector 22 is formed as a plug that connects theneurostimulator 50 to a lead set 24. In an embodiment, the lead setconnects to a first lead 84 which connects to a surface stimulator TENSelectrode 88 and a second lead 86 which is multi-stranded and branchesinto individual wires 86 a and 86 b, which may be single ormulti-stranded, and which provide the stimulation signals to two needleelectrode clips 26 a, 26 b. In an alternative embodiment, stimulation isonly delivered to the SAFN and a single wire 86 b, clip 26 b, and needleelectrode 28 b are provided. In other words, lead set 24 can communicatethe stimulation signal to the TENS electrode 88 and only to one needleholder 26 b, when only 1 percutaneous needle stimulator is used. Thesystem 10 may also be designed so that stimulation signals travelbetween the two needle electrodes 28 a, 28 b and a TENS electrode 88 isnot provided.

In the illustrated embodiment, needle electrode 28 a is insertedpercutaneously at a first location cephalad and posterior to the medialmalleolus, while needle electrode 28 b is inserted at a second locationto stimulate the SAFN, such as a location cephalad and anterior to themedial malleolus. The surface electrode 88, is positioned on the medialsurface of a foot of a patient 6 (other locations below or above theankle are also viable).

The display 20 shows a setting of “6”, reflecting amplitude or strengthof the stimulation signal applied at needle electrode 28 b for “SF”(i.e. SAFN) stimulation, while “10” reflects amplitude of stimulationapplied at the PTN site. The user has selected a stimulation protocolparameter value of “Same” which indicates that the stimulation issupplied to the SAFN and PTN at the same time, rather than “Alt” whichwould cause the sites of stimulation therapy to alternate. Alternatingmay include, for example, periodically stimulating for 5 minutes at thefirst target site followed by 5 minutes at the second, and so on.Alternating can also include stimulating at 10 Hz at both SAFN and PTN,with two stimulation signals that are time lagged to be out of phasesuch that the combined signal of the 2 interleaved series of pulses is20 Hz.

The display 20 can also indicate additional information such as a timervalue showing the duration of the therapy that has occurred (or theduration remaining), remaining battery charge, stimulator and/or sensorimpedance values, errors or faults (e.g., the neurostimulator did notreceive a scheduled maintenance or calibration). Information aboutwireless data and/or power communication strength (or connectionstatus), related to communicating power or data signals betweendifferent component of the neurostimulation system 10 and/or theneurostimulator 50 may also be shown. In addition to the display 20, theneurostimulator 50, can also use LEDs 92 a/156 situated on the housing12 in order to indicate a status of a measure such as impedance (e.g.green=good) or to alarm/alert the user about the status of therapy ordevice operation. The display 20 can be much larger than that shown inthe figure, and may be supplied on a user programmer 70 to enable clearpresentation of graphs and tables related to usage and compliance. In anembodiment, the display 20 can also display treatment creditinformation.

In alternate embodiments, either the graphic display 20 or some of theuser interface controllers may be realized as detachable from theneurostimulator housing 12. For example, the neurostimulator 50 may becontrolled by a user who has established wireless communication linkbetween it and a smartphone, tablet, laptop or other device, that mayserve as type of user programmer 70. Remote controlling of the device 50can be provided in addition to, or as an alternative to, the user inputbuttons 18 and display 20 on the housing 12. The neurostimulator 50 cancommunicate using wireless signals (e.g., infrared, Bluetooth, WIFI) orby wired connection, and can send data over the internet. A user'slaptop can be provided with a software application that providesinstructions to a processor for linking with, and subsequently controlof, at least one neurostimulator 50 as well as serving as adisplay/controller device. Either the neurostimulator or the linkeddevice can operate to notify a user (patient or administrator) bysending a visual, sonic, or other alert signal indicating a status orparameter value related to the provision of treatment using the userinterface module 76 and related alerting components 156.

Typically a stimulation signal with a fixed frequency (e.g., 20 Hz and apulse width of 200 msec) is increased until a behavioral response isseen such as flexion of the big toe or fanning of all toes becomesvisible, or until a subjective response is made (e.g., tinglingsensation is reported radiating towards the foot or toes). However insome patients, such as those with diabetes and various neuropathies, asubjective report may not be accurate or subjects may be unsure ofwhether a nerve is being stimulated for various reasons. Using sensordata can enable the detection of a quantitative measure such as a motorevoked response. In an embodiment, a second connector 23 connects theneurostimulator 50 to a lead set 85 which connects to at least onesensor such as a disposable TENS surface electrode 88 b. In order tomonitor nerve or muscle activity (e.g., EMG), the TENS electrode 88 bcan be realized with two electrical contacts. Alternatively, twodisposable TENS surface electrodes can be attached to the lead set 85.The neurostimulator 50 is configured to provide sensing and evaluationof a signal related to the provision of therapy, such as an EMG signal,using the sensing and processing modules 55, 58 in order to detect aperson's foot twitch (toe flex or fan, or extension of entire foot). oftoes in response to the stimulation of the PTN. Alternatively, measuring“muscle twitch” activity could occur using a strain gauge embedded witha sock or realized in an adhesive band-aid like form factor (which maylook like a surface electrode and use a bonded metallic strain gaugeddesign). Flexion or twisting of the strain gauge will cause change involtages that signals efferent activation.

FIG. 2 shows an alternative embodiment of a neurostimulation system 8for stimulating a first and a second nerve target in a first and secondleg of a patient. In this case the first target is an anterior branchSAFN target on the first foot (left side of figure) and the second is aPTN target on the second foot (right side of figure). A first and secondneurostimulator 51 b, 51 a are configured to provide stimulation to theSAFN via first needle stimulator 28 b and PTN using second needlestimulator 28 a (the end of the conduit 86 can be attached to a needleholder which, in turn, attaches to the needle 28, as in FIG. 1, but thisis not shown to avoid cluttering of the figure). As shown, the topsurface of the neurostimulator has displays and buttons and faces awayfrom the page. A disposable TENS electrode 88 a, 88 b can be attached tothe bottom surface of each neurostimulator 51 a, 51 b (e.g. theelectrode can snap onto an electrically conductive snap on the bottomside of the stimulator) in order to complete the stimulation circuit foreach foot. This configuration may be useful, for example, in patientswho are receiving stimulation therapy for both the SAFN and PTN, but whohave trouble tolerating (or have difficulty in being able to distinguishor assess) stimulation of both targets in the same leg. In analternative embodiment, stimulation is only delivered to the SAFN ofboth the left and right leg by neurostimulators 51 a,51 b.

Although a neurostimulator 51 b and its associated lead set 86 can bedesigned to provide stimulation of two or more stimulators 28 (as shownfor the system 10 of FIG. 1), there may be manufacturing and regulatoryadvantages to use a neurostimulator design that has already beenapproved by regulatory agencies for stimulation of a single site on oneleg and also factors related to patient comfort. Additionally, usingneurostimulators that have hardware, software, and protocols designedfor stimulation of a single site may be easier than designing a morecomplicated stimulator and user interface to stimulate more than onenerve target using a single stimulator. For at least these reasons, thesystem 8 can use neurostimulator embodiments that provide for jointoperation of, and/or connection between, two or more neurostimulators.

When two neurostimulators 51 a, 51 b use a pay-per-use, orpay-per-therapy-session, or other treatment-credit-based system, then atherapy protocol which includes stimulating two different targets insingle patient may require certain features to avoid problems that wouldotherwise occur. For example, although two stimulators are being usedduring a single treatment, it may not be desirable or appropriate tocharge for two different treatments and decrement the treatment creditsby 2 rather than 1. Several solutions are provided by the systems andmethods disclosed herein. In an embodiment a user/physician programmer70 may communicate in a wired or wireless manner with the payments andpermissions modules 202 of the first and second neurostimulators 51 a,51 b such that both neurostimulators can be activated to provide atreatment but only one neurostimulator will have its treatment creditvalue decreased. In the figure the neurostimulator on the right side ofthe figure has had its credit reduced by 1, to 15, while theneurostimulator on the left remains at 16 credits during the provisionof the current treatment. Alternatively, the user/physician programmer70 may be responsible for management of the treatment credits and cansend activation codes to the neurostimulators 51 a, 51 b which simplyobtain permission from the user/physician programmer 70 to operate toprovide treatment. Alternatively, one of the first and secondneurostimulators 51 a, 51 b is designated a ‘Master’ device while theother is designated a ‘slave’. The designation can be implemented usingeither hardware or software or both, and may be realized as part of thepayments and permissions module 202. For example, the master devicekeeps track of the payment credits and the slave device is controlled bythe master device, and may not be used or controlled in the absence ofthe master device. In an alternative embodiment, a high frequency lowamplitude signal can be transmitted by one stimulator and must be sensedby a second stimulator in order to ensure the two stimulators areattached to the same person. The signal can be transmitted and receivedwirelessly using near range communication by the communication modules68, or can be transmitted by one stimulator 51 a through the patienttissue and sensed by the other stimulator 51 b, whose sensing module 55is configured to detect this signal. Using a treatment credit system forpayment may be more easily applied to stimulation of 2 or more sitessince using a needle stimulator with a fuse may double the cost oftreatment when 2 sites are used.

In embodiments, various limitations may be imposed by the payments andpermissions module 202 to deter fraudulent treatment of two patientswhile only being charged for 1 treatment. For example, both stimulatorscan be simultaneously activated to provide therapy, but an operationlimitation requires that the start of therapy must occur within 5minutes of a communication session with the user/physician programmer 70for both a first and second neurostimulator 51 a, 51 b. Alternatively,the first and second stimulators 51 a, 51 b can be required toperiodically attempt communication with each other during the provisionof a therapy session and if this is not successful (e.g., for at least 1of 4 attempts) then it may suggest that the devices are being used in 2different locations with 2 different patients. If this requirement wasnot met, then the system 8 can be designed so that the “activation” ofat least one of the two neurostimulators is halted so that it does notprovide therapy or an alert signal is sent indicating that the twodevices are not communicating correctly. Wired or wireless communicationcan be provided by the communication modules 68 of the neurostimulators,and also of the programmer 70. A near field wireless technology can beused to establish a communication channel that allows for approximatelyonly, for example, a 1 to 2 foot range for communication in order toensure that the two neurostimulators are in close proximity.Additionally, a conduit 90 such as a microUSB, or custom, cable can beinserted into one of the I/O ports 114 a of each neurostimulator, andthe two neurostimulators can communicate in a wired manner to allow thetherapy to be delivered using the appropriate allocation of a singletreatment credit.

The neurostimulators 51 a, 51 b and a user/physician programmer 70(which is a device such as a computer having controller circuitry suchas a processor, display, memory, power source, communication means, andother circuitry as is well known) can communicate to transmit dataand/or power signals to each other. The user/physician programmer 70can, in turn communicate with a remote management computer 71, and canrelay communication between other system 8 components. The managementcomputer 71 may be at least one computer, or part of a network ofcomputers that operate software instructions under control of theirprocessors to manage aspects of the therapy such as purchase anddelivery of payment credits and/or recording, assessing, and reportingdata related to times and durations when therapy was provided. Themanagement computer 71 is able to set flags and operational valuesrelated to use, payment, and compliance, as well as other relevant data.In an embodiment the user/physician programmer 70 can communicate with aremote management computer 71 to transmit a signal over a computernetwork to submit a request for one or more treatment credits withassociated reimbursement codes that are related to providing stimulationusing either one neurostimulator or more than one neurostimulator (orone stimulator which is being used to treat one or more sites). In thelatter case, in an embodiment, the remote management computer 71 canprovide the user/physician programmer 70 with therapy credit that isdesigned to allow for the activation of two neurostimulators to be usedin treatment of a single subject. In additional embodiments, rather thanone or more neurostimulators keeping track of the therapy credits, theuser/physician computer 70 can manage the treatment credit usage. Forexample, the user/physician computer 70 can provide an activation codesignal to the two or more neurostimulators and then operate itsprocessor to decrease the treatment credit value stored in its ownpayments and permissions module. For tracking purposes each treatmentcredit may have a unique ID value. The ID value may contain fields forinformation about when, where, and how the credit was purchased and/orused. The ID value accordingly may have a plurality of fields, some ofwhich are modifiable by a programmer or neurostimulator.

When the neurostimulators 51 a, 51 b are used in the setting of apatient's home, or are otherwise used outside of a clinic by thepatient, to provide therapy stimulation then the user/physicianprogrammer 70 can communicate with the neurostimulators 51 a, 51 b aswell as directly with a remote management computer 71 that managesaspects of the therapy. This is true regardless of whether the therapyis at least one of: transcutaneous (e.g., via electrical, vibratory,magnetic, or other modality), occurs under control of an external devicethat provides control and/or power of an implantable device thatprovides therapy, occurs by the programmer 70 communicating with animplantable device to adjust the operations relate to therapy, orotherwise. Additionally, the user/physician programmer 70 in a patient'shome may communicate with a remote physician programmer 70′ at thepatient's physician's office which may, in turn communicate with theremote management computer 71 in order to manage the patient's therapy.In other words, the physician programmer 70′ at the physician's officecan act as a relay between the user/physician programmer 70 at thepatient's home and the management computer 71. The management computer71 may be operated by a medical company that charges users or doctorsfor ongoing use, per-treatment use, time-based rental, purchase, and/orperiodic activation of the neurostimulators for selected intervals oftime (e.g. 1 hour or 1 month). The management computer 71 may in turnsend and receive information with computers of insurance companies inorder to carry out operations related to insurance monitoring andreimbursement. Rather than a user programmer 70 communicating directlywith a medical company or insurer, a clinic may prefer the userprogrammer 70 to communicate with the physician programmer 70′ at theclinic, which in turn communicates with the management computer 71. Thisindirect route of sending data over a computer network, by routinginformation through the clinic may be preferable for the clinic (who maywish to charge or monitor user treatment) and also for a medical companythat may choose not to directly communicate with or receive data frompatient devices. Additionally, during a periodic exchange of datarelated to device payment, data relating to device use (stimulationtimes, durations, and stimulation parameters) can be exchanged. Thetransmission of user data from user devices to a physician programmer70′ may provide a doctor with the opportunity to review the usage of aparticular patient rather than requiring this information to be acquiredduring a patient visit. In some instances, this may reduce the need formore frequent patient visits. In an embodiment, user compliance data(e.g. whether a patient successfully self-stimulated at least a minimumnumber treatment sessions per week) can be at least periodicallycommunicated with either a doctor's office or an insurance company orboth.

When a needle is used to percutaneously stimulate the saphenous nerve itmay use a conductive tip that is below a non-conductive region to avoidstimulating near the surface of the skin which may cause pain. In anembodiment, a pulse generator of a stimulation module 54 of theneurostimulator 50 is electrically coupled to both an electrode TENS pad88 and a percutaneously inserted needle electrode 28 b for stimulatingthe SAFN. During stimulation treatment, current pulses of thestimulation signal traverse the stimulation site by passing from theTENS electrode 88 to the conductive portion of the needle electrode 28b. Additionally, the subject system can be configured to operate aneedle stimulator with two contacts (e.g., conductive annular rings)formed on an insulated needle that serves as a bipolar electrode. In anembodiment, two conduits can connect to two contacts on the top of theneedle stimulator which respectively connect to the first and secondannular ring. The needle does not need to be conductive and can be madeof plastic or other suitable non-conductive material that has electricalrouting disposed along its length provided by conduit means. When twoneedle electrodes are used, the current pulses can between the TENSelectrode and both needle electrodes 28 a, 28 b. In some stimulationprotocols, the TENS electrode 88 and the needle electrodes 28 a, 28 bare designated as anode and cathode, respectively, while in others thesedesignations change over time. In an embodiment, the TENS electrode isnot used, and the current pulses can travel between the two needles 28a, 28 b.

FIG. 3a shows an embodiment of neurostimulation system 8 applied so asto stimulate a first and a second target in the same foot of a patient6. A first and second neurostimulator 51 b, 51 a are configured toprovide stimulation to the SAFN using needle stimulator 28 b and PTNusing needle stimulator 28 a. A disposable TENS electrode 88 a isattached to the bottom surface of neurostimulator 51 b in order tocomplete the stimulation circuit with needle stimulators 28 b, 28 a.There may not be sufficient surface area on the medial side of apatient's foot for a both stimulators to be attached. Further due topatient comfort, or for other reasons, it is not preferable for thesecond neurostimulator to be placed elsewhere on the patient.Accordingly, a neurostimulation linking system can be realized using acommunication cable 90 which connects to I/O connectors 114 a providedin the housing 12 of each neurostimulator (see FIG. 2). In anembodiment, I/O connectors 114 a connect to various components of theneurostimulators 51 b, 51 a including a circuit 145 (see FIG. 9) thatelectrically joins the circuitry of the stimulation module that connectsto the TENS electrode used for the neurostimulator 51 a, to theelectronics connected to the TENS electrode 88 a of neurostimulator 51b. This allows the disposable TENS electrode 88 a of the firstneurostimulator to serve as the return path for the secondneurostimulator as well. The neurostimulation linking system can also bedesigned to enable data signals sent using wires of the communicationcable 90 such as those related to the operation of the payments andpermissions modules 202 of both neurostimulators. Communication cable 90enable the modules of the two systems to collaborate to providestimulation while managing treatment credits appropriately (e.g.,decrementing the treatment credits of only 1 of the neurostimulators dueto the provision of a single therapy session).

An alternative system and method of connecting the two neurostimulators,which also does not require the second neurostimulator to be attached tothe patient's foot, is shown in FIG. 3b as a TENS electrode linkingsystem. In this example embodiment, two disposable TENS electrode padscan be attached via their electrically conductive snaps 89 a,89 b to thebottom of the two neurostimulators 51 a, 51 b as would typically be donewhen providing therapy to a patient. The first TENS electrode pad 88 bhas a bottom side that makes contact with the patient's skin and a topside that snaps onto the first neurostimulator 51 b to provideelectrical connection from the neurostimulator to the patients skin. Thefirst TENS electrode pad 88 b also has a connector for connecting to asecond TENS electrode via a linking cable 91. The second neurostimulator51 a also has a TENS electrode pad 88 a that can then be electricallyand physically connected to the first TENS electrode pad 88 b by alinking cable 91. In this embodiment, the second TENS electrode pad 88 ais not attached to the patient and therefore does not require its bottomsurface to be adhesive or electrically conductive, although it can be.In an embodiment, the second TENS electrode pad 88 a is realized simplyas a snap-type connector that snaps to the bottom of the neurostimulator51 a and connects to cable 91. Alternatively, when only oneneurostimulator 51 b is used, it may be designed to connect to electrodepad 88 b to provide stimulation to a patient's skin, and may have 2stimulation channels for stimulating at 2 different needle electrodesites, both of which are commonly referenced to the pad 88 b.

FIG. 4 shows an embodiment of a neurostimulation system applied to a legof a patient 6 for providing percutaneous stimulation. Theneurostimulator may be configured to provide stimulation of the SAFNusing needle stimulator 28 b at a first location near the knee—at aposition 2-3 inches distal to the knee and on the medial surface isshown. More specifically, the SAFN can be targeted by inserting a 34 Gneedle electrode within a ‘notch’ region located between the medialcondyle of the tibia and the superior border of the medial gastrocnemiusmuscle. It is oriented in the anterior-posterior direction and has awidth of approximately 1.5 cm. In over 20 patients the notch wasrecently found by the inventors to easily and quickly provide a site forsuccessfully stimulating the SAFN using percutaneous stimulation, withpatient confirmation of SAFN stimulation achieved when the sensed anelectrotactile stimulation was experienced as radiating towards, andeven into, their foot (MacDiarmid , Yoo and John, Percutaneous SaphenousNerve Stimulation: A New Technique in the Treatment of OveractiveBladder, In Prep, incorporated by reference here). Further in this studywe found a robust treatment response with patients showing improvementwhich appears stronger than that typically seen with tibial nervestimulation. In a system and method of the current invention, users areinstructed to use this area to provide stimulation. Additionally, oralternatively, PTN stimulation may be provided using needle stimulator28 c at a second location cephalad and posterior to the medial malleolusto stimulate the PTN. A TENS electrode 88 placed on the medial aspect ofthe foot (or between the two electrodes, near the tibia at about thelevel of mid-calf, not shown) may be used to complete the stimulationcircuit in the case where one or more needle stimulators are used.Alternatively, the stimulation pathway may be defined simply using thefirst and second needle electrodes 28 b,28 c . Additionally, the firstneedle electrode and the TENS electrode near the calf may be define onecircuit and the second needle electrode 28 c and the electrode 88 maydefine a second stimulation ciruit. Stimulation of the SAFN using aneedle electrode near the knee has been previously used to provideelectrical-nerve stimulation for target site validation when providinglidocaine nerve block of the foot (Benzon et al. Comparison of thedifferent approaches to saphenous nerve block. Anesthesiology. 2005March; 102(3):633-8). Accordingly, methods for determining the locationof the SAFN have been successfully practiced using imaging modalitiessuch as fluoroscopy, ultrasound, and/or electrical stimulationtechniques, which can also be incorporated into the currently disclosedtherapy for overactive bladder or other disorder. Typically, however,subjective responses such as the feeling of tingling being reported by asubject (SAFN) can be used to select and confirm appropriate targetlocations for providing therapy. For the PTN the observation of motorevoked muscle activity can be used to select and confirm appropriatetarget locations for providing therapy. SAFN and PTN targets should beconfirmed and stimulation parameters set up separately prior toproviding therapy. Further, a method for determining correct placementof an implanted device may include assessing candidate locations usingpercutaneous stimulation. The site producing highest tingling or thelowest threshold of amplitude at which tingling is detected maybe assuitable site for implant.

Rather than stimulating both the SAFN and PTN, stimulation can occur attwo or more different locations along the SAFN and its branches as ameans of increasing the therapeutic effects. One needle electrode cantarget the SAFN trunk (28 b) while the second needle electrode 28 c cantarget a different area of the SAFN trunk at a location about halfwaybetween the knee and medial malleolus or the anterior SAFN branchlocated cephalad and anterior to the medial malleolus. The second needleelectrode 28 c can also be positioned to stimulate the posterior SAFNbranch (and/or the PTN) at a location cephalad and posterior to themedial malleolus, although determining co-activation may be difficultdue to motor activity. Alternatively, the second needle can be locatedabove the first and can target the infrapatellar branch or other SAFNtarget above, at, or below the level of the knee. The method of FIG. 13Acan be used to position the needle electrodes when providing stimulationat two or more stimulation sites.

As the inventors have described previously (see U.S. Pat. No.9,610,442), due to the different profile (i.e., frequency responsecurves) produced when rat SAFN and PTN nerve targets were stimulated, aswell as the different spinal projections, it may be that the bladderreflex circuits of the SAFN and PTN are at least partially independent.Accordingly, rather than stimulating only the SAFN, additionalimprovement may be obtained when stimulating both the SAFN and PTN aspart of treatment. It is also worthwhile noting that the acute andprolonged responses to bladder stimulation were different and suggestthat individual patients may receive greater benefit when using SAFNrelative to PTN (although potentially the opposite may be true in somepatients), to treat acute urge incontinence symptoms, while greaterprolonged response may be obtained when stimulating the other target.

FIG. 5 shows an embodiment of a neurostimulation system applied to a legof a patient 6 for providing TENS of the SAFN. The neurostimulator 50may be configured to provide stimulation of the SAFN at a first TENSstimulator 30 b at a location on the medial aspect of the leg near theknee, and/or a second TENS stimulator 30 c at a location cephalad andanterior to the medial malleolus, and/or a third TENS stimulator 30 dplaced at a location midway between the locations of stimulators 30 band 30 c (and also which may typically be positioned closer to the tibiato lessen concurrent simulation of calf muscles). A TENS electrode 88can also be placed on the medial aspect of the foot in order to completethe stimulation circuit or pairs of electrodes on the leg may serve toprovide two independent stimulation signals (e.g. between 30 b and 30 d,and between 30 c and 88). Alternatively, the stimulation protocol mayprovide stimulation with a circuit that may only include two electrodeslocated in approximately the shaded medial region of the leg “medialtarget region”. In an embodiment, additional TENS stimulators may beused along the medial aspect of the leg starting approximately at thelevel of the knee in order to stimulate the SAFN. Electrodes can bepositioned above the knee or on the lateral surface of the leg, butthese may stimulate the sural nerve or other targets rather than theSAFN. If electrodes are placed on both the lateral and medial aspect ofthe leg, the stimulation pain threshold may be lower for the lateralsite. In some people, this may limit the stimulation level that is ableto be provided to the medial target.

The TENS stimulators on the leg 30 b, 30 c, 30 d may be anode, and theTENS electrode on the foot 88 being a cathode (or vice versa), or thisstatus can change with the characteristic of the pulses of thestimulation signal. Only two TENS electrodes on the leg may be used toprovide stimulation. Alternative configurations for TENS electrodes(e.g. bipolar pairs, different sizes of TENS electrodes that change thecurrent density, etc) are well known, have been described in the priorart related to providing TENS stimulation, and can be used with theclaimed system.

In embodiments, any of the TENS electrodes 30 a, 30 b, 30 c, can also beallocated to serve as a patient ground or be used to measure electrodeimpedance or nerve/muscle activity before or during stimulationtreatment (e.g., between stimulation intervals).

SAFN stimulation using TENS with electrodes located at approximatepositions 30 b and 30 d in the figure has been used to provideelectrical stimulation of the SAFN in a study conducted by one of theinventors pilot results collected in healthy control subjects who didnot suffer from bladder disorders such as OAB, showed that 15 out of 15subjects (100%) were able to report a cutaneous sensation of tingling(paresthesia) radiating down their lower leg during stimulation (Eshani,Hunter, Hassouna, and Yoo, Investigating the Feasibility of Non-InvasivePeripheral Nerve Stimulation for Treating Overactive Bladder, In Prep.).Most participants indicated paresthesia down to the level of the medialmalleolus, while some subjects indicated that paresthesia extended totheir hallux. FIG. 6B. shows shaded anatomical plot of the sensationperceived during SAFN stimulation, showing that as the amplitude wasincreased from threshold skin (Tskin) to threshold where discomfort wasexperienced (Tlimit), the evoked sensation spread from under thepositions of the electrodes across the entire medial aspect of the lowerleg, down to the ankle or hallux reflecting recruitment of the SAFN(N=15 subjects, but key=14 since there was not common overlap ofsensation across subjects).These results suggest, for the first time inhumans, that the SAFN trunk could be successfully activated by externalTENS stimulators (which were oriented vertically and positioned mediallyon the upper leg), below stimulation amplitudes that can causediscomfort or pain to the subject. Furthermore, in a subject who did notdetect this sensation at the initial stimulation location, moving theTENS electrode to a second target site and trying again resulted inpositive electrical recruitment of the SAFN at stimulation levels belowpain. Review of individual data suggested that while sensory recruitmentthreshold was lower than nerve recruitment threshold, and both of thesewere lower than pain threshold, it was not possible to predict onethreshold from knowing the other (i.e. nerve recruitment threshold couldnot be easily used to accurately predict pain threshold). These resultssupport that TENS-based SAFN stimulation at targets selected between theknee and cephalad to the medial malleolus are easily found and may beeffective in the treatment of OAB.

Although the maximum amplitude tolerated by participants in this studyranged from approximately 20 mA to 60 mA, other stimulation parameters(such as frequencies between 2 Hz and 50 Hz, or stimulation durationbetween 15 minutes to several hours) may have different maxima and maybe assessed, selected, and then used in patients during therapy, orchanged as therapy progresses. In embodiments, the stimulation waveformscan be a carrier waveform with frequency in the kHz range, such as a5,000 Hz-50,000 Hz (or higher), that is modulated by an activationsignal delivered at 5 to 20 Hz. Additionally, other characteristics suchas amount of body fat, edema, impedance of skin, and conditions such asdiabetes that affects sensitivity to pain may require adjustments in thestimulation waveforms or sites used during therapy for individualsubjects, and may be perceived differently than (or not perceived at allsuch as in the case of some diabetic patients or patients with othermedical problems) the stimulation waveforms used in the above study inhealthy, young subjects. Additional therapeutic benefit may be obtainedby providing the TENS stimulation bilaterally in either a concurrent oralternating manner, with respect to a single treatment session or acrossindividual treatments. Additionally, since the SAFN has been used tosuccessfully produce paresthesia, TENS based stimulation may be used todecrease discomfort associated with foot pain as well as providetreatment in OAB. In an embodiment the maximum amplitude provided by aTENS neurostimulator may range from 100 mA to 200 mA.

Percutaneous TN stimulation therapy treatment sessions typically occurfor about 30 minutes once per week during an induction phase, and onceper month during a maintenance phase. In contrast, during treatment withTENS in a home setting, subjects may provide SAFN stimulation for atleast 30 minutes every day, every other day, or at least once per weekduring induction. This can occur just as frequently or less frequently,for continued benefit during maintenance. Therapy may also includeproviding TENS during sleep for least one night per week. Especiallyduring long (e.g. >1 hour) therapy periods, the neurostimulator 50 mayrealize a stimulation protocol that provides intervals ofnon-stimulation between the stimulation intervals, for example, 30minutes on, then 2 hours off, then 30 minutes on, etc. This may provideadvantages of both less skin irritation and can also extend periodsbetween recharging or decrease the size of a battery.

The neurostimulator 50 can be programmed with various “SLEEP” protocolsand features. These can be selected by a patient at bedtime or beprompted or selected automatically by the system as a function ofclock-time. The SLEEP protocol can cause the neurostimulator 50 togradually increase to a selected therapy amplitude across a period of 1hour, and/or delay onset by 1 hour, in order to decrease the risk ofinterfering with a subject's sleep. The protocol may also cause thestimulation amplitude to gradually ramp down after an interval that isdefined to end an hour or so prior to when the subject is expected towake up in order to deter early awaking. If the system is provided with,or is in communication with, a sensor (e.g. EEG, EKG, strain, oraccelerometer sensor), and a processor is provided in a sensing module55 that is able to algorithmically assess arousal level, sleep, or sleepstage based upon sensed data, then TENS stimulation may only occur whenevaluation of sensed data meet a selected criterion. For example,stimulation may only be provided during certain sleep/arousal stages oronly when the subject is experiencing restful sleep (e.g., leg movementmeasures remain below a selected threshold). A stimulation protocol thatis defined for providing stimulation for longer periods (e.g. severalhours at night) can use different stimulation signals than those usedduring a 30 minute therapy session, For example, the amplitude of thesignals may be lower those used for 30 minute sessions.

Patient Safety Across Stimulation Type.

Stimulation signal amplitudes may be lower when the neurostimulator 50uses needle electrodes rather than TENS electrodes. Accordingly, inorder to provide for patient safety and deter unwanted or unintendedstimulation signals from being erroneously used, a number of hardwareand/or software safeguards can be used. For example, a lead set 24 thatis attached to the device by plug 22 uses a lead set or plug forproviding TENS stimulation that is different, and may even connectdifferently to the system, than that which is used to providepercutaneous stimulation. Additionally, these two different types oflead sets/plugs can contain circuitry that adjusts the amplitude of thestimulation signal output by the device 50 so that it is appropriate tothe therapy being delivered to the patient. The neurostimulator mayallow users to toggle the control module 52 to operate in a percutaneousmode or TENS mode. Each mode has a set of one or more stimulationprotocol parameters that create stimulation waveforms that areappropriate for the two different types of stimulators (e.g., voltage,current, pulse-width, or duty cycle). However, for safety or otherreasons it may be preferable to use two different lead sets that inhibita user from accidentally providing a stimulation signal that is higheror lower than what is intended. The plug 22, can also communicate, orotherwise operate in conjunction with, internal modules of the device inorder to adjust the amplitude, or maximum amplitude that is permittedwhile the plug is attached to the housing 12. In an additionalembodiment two different plug+lead sets can be used, where the plug thatis used during TENS stimulation fits a first connector of the system anda different shaped plug fits a second connector of the system. In anadditional embodiment an adaptor can be provided for a plug that is usedduring percutaneous needle stimulation that fits a first connector ofthe system (and attenuates the stimulation signal by a selected amount)and the plug for the TENS lead set can be attached directly to aconnector of the system 10. The lead sets used for percutaneousstimulation may have circuitry that attenuates the strength (e.g.,voltage, current, pulse width) of the stimulation signal output from thedevice 50, while the TENS lead set does not have this additionalcircuitry. Alternative methods for providing patient safety aredisclosed later in this specification.

FIG. 6A shows an embodiment in which TENS stimulators are applied to theback of a patient in order to stimulate either lumbar and/or thecombination of lumbar and sacral nerves. Current investigations ofsacral stimulation therapy using TENS (e.g. ClinicalTrials.govIdentifier: NCT01940367) instructed subjects to place surfaceelectrodes, 2″×2″ in diameter, over sacral foramen S2-4, bilaterally,using 2 channels (4 electrodes total). Approximate locations are overposterior superior iliac spine and inferior lateral angle of sacrum. Asis shown in FIG. 6A, using TENS electrodes more cephalad to thelocations used to stimulate sacral targets 36, such as locations 34 overthe lumbar sites L2-L5 can be used instead of, or in addition to, thecurrently evaluated approach to provide improved therapy. During theprovision of therapy, stimulation may be provided using differentpatterns. For example, stimulation can be sequentially applied tocontralateral electrode pairs (at the same level of the spine) ratherthan concurrently (e.g. L2 left and L2 right, then L4 left and L4right), or ipsilaterally (e.g., L2 and L4 left, then L2 and L4 right),or can be applied to single targets (e.g., L2 left with an electrodeplaced on the patient's thigh to close the circuit). Additionally, in anembodiment, treatment using the lumbar TENS sites can be used inpatients who do not respond to stimulation of other targets such as atsacral target sites.

Patient Compliance

In a trial, or clinic-based, setting the detection of non-compliance mayallow for corrective measures and interventions that can ultimatelycause therapy to be successful rather than fail. When providingstimulation at home, rather than in a clinic, monitoring and promotingpatient compliance can be essential. Especially in more severe cases ofOAB, an increased amount of stimulation may be needed in order to obtaintherapeutic benefit, rather than 30 minutes once or twice a week.Patient compliance may be a challenge both for TENS, magneticstimulators (e.g. TMS devices) and for ‘implantable’ therapies that arepowered by, or controlled by, external components of theneurostimulation system. In therapy systems that stimulate targets suchas the PTN or SAFN and do not provide for an internal battery inimplanted components, the patient must remember to activate an externalcontroller in order to activate the implanted neurostimulator. Theprovision of a compliance module 200 is important because it is wellknown that patients can be inaccurate about their actual compliance, andthis can be a greater concern for older OAB patients. It may beimportant for a doctor to be able to accurately assess patientcompliance, rather than simply the reported compliance, in order todetermine if a patient is not responding to therapy due to complianceissues or due to other reason such as lack of a treatment response in acompliant patient. Accurately tracking compliance may also be importantin assessing efficacy in clinical trials where subjects are expected toprovide self-stimulation outside of a controlled setting.

In embodiments of the current invention the user/physician programmerworks with an implantable neurostimulator. An example the Stimguard orBluewind systems which are undergoing clinical trials and another iseTENS, which we have previously described. It is typically not usefulfor a doctor to assess patient compliance in self-stimulation during aclinic visit by patient report which may not be accurate. Existing TENSsystems do not allow a doctor to assess patient compliance outside oftheir clinic visits using remote monitoring. Accordingly the subjectinvention is provided with functional modules that address currentlimitations related to managing and augmenting patient compliance.

In an embodiment, a compliance module 200 is realized within at leastone component of the system 8 such as the neurostimulator 50, and/or theuser/physician programmer 70, and/or the management computer 71, andperforms operations related to patient compliance. The compliance module200 can operate, and work with the other modules of the neurostimulationsystem, in order to manage, monitor, track, promote, summarize, analyze,display, report, transmit, process, and alert to, aspects of patientcompliance (Give an example of each of these including sending to adoctor). Although existing TENS units can monitor patient usage in theform of total treatment time provided (e.g., in total hours) since thereset of a counter, there is no provision for many other characteristicsrelated to patient compliance. The compliance module 200 stores adetailed historical record of patient use and displays the actual usageusing metrics that reflect a per-hour, per-day, or per-week basis. Someadditional features and advantages of the compliance module 200 of thepresent invention, that address limitations of the use-counters ofexisting TENS devices are now further disclosed.

The compliance module 200 can alert a patient 6 by operating the userinterface module 80 or communication module 68 to provide an alertsignal to a patient about a scheduled therapy interval. The alert signalmay be communicated from a device of the system 8 to a patient'ssmartphone or may be realized as a sonic or visual alert provided by theuser/physician programmer 70. The alerts may be used to alert thepatient (or physician or other intended recipient) to compliancefailures when a compliance criterion is not met. A compliance failuremay occur if a patient fails to provide stimulation for one or morescheduled therapy sessions within a defined time interval (e.g. within24 hours after stimulation was supposed to occur), or in response tofailing to meet other compliance conditions as will be disclosed. Thecompliance module 200 can also alert a user to the approach of ascheduled stimulation session/time.

In embodiments, compliance module functions can be realized, at least inpart, by a customized application operated on a patient's smartphone.For example, an application running on a processor of a smartphoneaccording to instructions provided on computer readable media can causean alert signal to be issued to a patient or caregiver to remind about ascheduled therapy. The alert can be set to occur prior to a scheduledtherapy time (as a prompt), or at a selected time after the therapy ifthe patient did not provide correct or insufficient therapy (as areminder), or both.

A smartphone-based compliance application can be considered as onealternative embodiment of the compliance module 200, and may be operatedindependently or in combination with the compliance module 200 of thesystem. A smartphone compliance application that does not communicateand cooperate with the compliance module 200 of the neurostimulator maybe limited and may simply serve as a reminder-system, since while theapplication provides reminders to a patient it may not be able tomonitor and/or determine if therapy is provided by the system 8.However, an integrated system is preferred and wireless communicationbetween the neurostimulator 50 and a patient's smartphone can occur viaradiofrequency, Bluetooth, sonic, infrared, WIFI, or other one-way ortwo-way communication protocol.

FIGS. 7A and 7B show two embodiments of compliance screens that can beprovided using information generated by, stored, and operated upon bythe compliance module 200. FIG. 7A shows a month-calendar summary viewthat displays both total therapy per week (in minutes) as well asmaximum and minimum durations during which individual therapy sessionsoccurred. The weekly summary statistics are presented in the therapysummary table on the left hand side of the screen and include totalminutes per week, and the minimum and maximum durations for stimulationsessions provided by the system. Also shown in the bottom row of summarystatistics is the integrated time across the entire month, whichprovides a simple patient compliance measure that shows the totaltreatment time in hours.

There may be different compliance criteria that must be met in order forthe patient to be considered compliant. For example, a monthly therapycompliance criterion may require that at least 2000 minutes of therapybe provided each month. In this example, the patient has met thiscriterion successfully (i.e. the patient provided 2157 minutes).Alternatively, a weekly therapy compliance criterion may includeproviding therapy for at least 120 minutes per week. In this case thepatient did not meet this therapy compliance criterion in the 3^(rd)full week of April where only 60 minutes of therapy were provided. Thecompliance failure is reported by a shaded value of “60”. A therapycriterion can also exist for a time of day, for example a therapycriterion can require a patient to have at least 3 sleep/night sessionsof at least 5 hours each week. Therapy compliance criteria as well ascontingent actions which occur if one or more criteria are not met canbe selected or adjusted by a user such as a doctor, caretaker, orpatient. A password or other permission schema may be used to restrictaccess to the operations that allow therapy criteria to be adjusted.Additionally, summary statistics can be calculated and displayed by thecompliance module 200 that compare the times and durations a patientprovided therapy in relation to pre-set treatment schedules. Therapycompliance criteria can be set for minimum/maximum durations,stimulation amplitudes to be used during treatment, and othercharacteristics.

FIG. 7B is an alternative view of compliance data monitored, stored, andsummarized and displayed by the compliance module 200 which in thisexample is shown in a weekly view that also shows the hours of each dayof week that therapy was provided. This view can be obtained by apatient (or doctor) by clicking on any week of the calendar shown inFIG. 7A. Night time data (times when the patient is typically sleepingor as determined by analysis of sensed data such as accelerometer data)can be shaded in one color (e.g., grey boxes), and times when thepatient is typically awake can be shaded in a different color such aswhite.

Either an implanted neurostimulator or an associated external devicethat provides power/data signals to control therapy can operate acompliance module 200 to generate and log in device memory a record ofoperation. It can further compare use information to compliance criteriato monitor, generate and store a log related to, assess, transmit,promote, alert to and display compliance or lack of compliance.

The compliance module 200 can monitor and assess a patient's complianceusing various compliance criteria, such as the following:

A daily compliance criterion can include a minimum amount of time perday during which therapy must be provided, for example, at least 30minutes of approximately continuous stimulation, using a minimumamplitude, on a given day.

A nightly compliance criterion can include a minimum amount of time pernight during which therapy must be provided, for example, at least 6hours on a given night.

A weekly compliance criterion can include a minimum amount of timeduring the week during which therapy must be provided, for example, atleast 20 hours per week. Additionally, a weekly compliance criterion caninclude meeting the daily compliance criterion for at least a selectednumber of days (such as 3 days of the week). A weekly compliancecriterion can also require for example, at least 3 days of therapy andfurther require that a day with no-therapy occurs between each day oftherapy. A weekly compliance criterion can also require, for example,that the daily compliance criterion is met at least twice over thecourse of a week and the night criterion is met at least once.

A monthly compliance criterion can include a minimum amount of timeduring the month during which therapy must be provided, and may includeadditional compliance criteria such as that at least 2 of the 4 weeksmust be weeks where a weekly compliance criterion was met.

Compliance criteria can relate to stimulation protocols rather thannumber of treatments or total therapy duration. For example, acompliance criterion may require such characteristics as stimulatingboth legs instead of one leg at least once a week. A compliancecriterion can require a patient fill out an electronic bladder diary, aquality of life survey, or provide responses to Likert-type scales thatare provided by a device of the system 8 according to a schedule such asat least once every two weeks. A compliance criterion can require thatmore frequent stimulations such as every other day are provided at thebeginning of therapy and after an interval such as one month, can thenbe decreased to require a less frequent schedule of stimulation sessionsto be provided by the user. Compliance criteria can also relate to userswho take medication and can be calculated based upon user input queriesabout whether they have taken their medication. Accordingly,stimulation+medication compliance criteria can be operated upon by thesystem.

Similarly the system 10 may be programmed with a stimulation programthat is more frequent in the first days or weeks of therapy, and thenthis becomes less frequent only if the patient reports benefit inrelation to patient input such as responses to survey items provided bythe user interface module 80. Additionally, the system may query thepatient under control of the patient survey module 61 about symptoms andcan begin to decrement the frequency of the treatments after a minimumamount of time (e.g. 4 weeks) if the patient responses rating scales oranswers to surveys presented to the user are operated upon anddetermined to show improvement (e.g. QOL scores improve over a selectedamount). The patient alerting and compliance module 200 parameter valuescan then be adjusted accordingly.

In addition, compliance may relate to enforcement of compliancerestrictions. For example, the compliance module may dictate that apatient cannot provide therapy more than a certain number of timesper-day or other interval. The restriction can be assessed by comparingusage to interval rules. Further the restriction can be a combination ofboth time and treatment strength and assessed using interval-strengthrules. For example, a patient who uses larger stimulation amplitude maybe restricted to a lower number of maximum treatments within a selectedtime interval. Unlike medication, where a patient ingests a certainnumber of pills over the course of a defined interval and must obtainrefills at the end of the interval, there may be no evidence of patientover or under usage of electrical therapy in the absence of thecompliance module 200.

The compliance module 200 allows doctors or patients to adjust howcompliance is managed by selecting what the compliance criteria are foran individual as well as how and when the therapy schedule may changeover time. Both usage and compliance can be tracked over time, and thiscan be displayed to a user or remotely to a doctor. The promotion ofcompliance can occur with setting reminder alerts to occur before ascheduled stimulation session, or after the time when this was scheduledif it did not occur, etc. Reports related to usage and compliance can bestored and transmitted over computer networks in order to allow forremote patient monitoring and management. The various features shouldimprove patient compliance.

In the case of patient non-compliance various operations may occuraccording to the compliance module 200 in conjunctions with the othersystem components and methods of the invention. For example, failure tomeet a monthly compliance criterion for X out of Y months, or for aselected number of sequential months, can result in the compliancemodule 200 causing an alerting module 204 to cause a signal to beprovided to the patient or medical care provider. Alternatively, acompliance module 200 algorithm may cause the neurostimulator todeny/restrict stimulation until it receives a reset signal from a remotephysician computer 70′. Additionally the patient prescription statusflag may be changed to inactive in the remote physician computer 70′. Inother words, if a patient is not compliant and then wishes to use aneurostimulator then they may first have to meet with their doctor todiscuss the non-compliance and have their device re-enabled. The doctormay need to submit the compliance record of the patient and evidence ofa patient visit in order to obtain an approval from an insurance carrierto re-activate a neurostimulator of a patient. This may further be tiedto requiring a new prescription be written and prescription statusupdated in the system.

The compliance module may operate to provide different alerting schemesfor treatment of different disorders. For example, if the TENS system isused for providing transcranial direct or alternating stimulation (i.e.tDCS or tACS) in the treatment of depression or anxiety, failure toadhere to a treatment schedule may result in the system communicatingwith a computer 70,70′ to alert a doctor or caregiver that a patient isnot complying with a therapy regimen. Alternatively, if the tDCS/tACS isused to provide cognitive enhancement, then no such notification mayoccur. In an embodiment, compliance operations relay upon timingcircuitry, such as a real-time clock, to calculate times and datesrelated to when and for how long stimulation was provided.

The payments and permissions module 202 can communicate with a remote aremote management (e.g., a computer of an insurance company) orphysician computer 70,70′ in order to ensure that a patient is in goodstanding before enabling the provision of therapy. For example, a remotemanagement or physician computer may assess whether 1. The patient hasmet various compliance criteria; 2. The patient has an activeprescription for the therapy from their doctor which has an associated“active” status flag that is set in the neurostimulator; 3. Insurance isin good standing; 4. The account associated with the neurostimualtor hasnot been flagged for any reason, such as a) doctor has failed to meetwith the patient for too long a time since prior visit b) theneurostimulator is scheduled for calibration/maintenance/replacement orc) the neurostimulator has sent flags related to device operation,faults, failure to meet calibration and/or self-test routines etc.

FIG. 8 shows a neurostimulator device 50 that can be used to realize themethods and systems of the current invention. The neurostimulator 50 isillustrated with a number of modules and components which may beincluded, omitted, or modified in various embodiments. The modulesprovide functionality to the neurostimulator and, while showndiscretely, may share software and hardware components with each other.Further, each of the modules may be realized within the neurostimulatorhousing, outside of the housing, or both (i.e. in a distributed manner).Modules may be realized jointly between the neurostimulator 50 and anexternal device such as a user/physician programmer 70 and can beredundantly provided within different components of the neurostimulationsystem. For example, an alerting module 204 may be realized within animplantable neurostimulator, an external neurostimulator, auser/physician programmer, and/or a remote management computer (or acomputer network of which it is a part).

The device 50 comprises a control module 52 with circuitry forcontrolling the various other modules of a neurostimulation system 8.For example, under its direction, the stimulation module 54 and sensingmodule 55 can be controlled according to user input commands and/ortreatment protocols and parameters stored in the protocols andparameters module 66. Treatment protocols can include stimulationprotocols, sensing protocols, alerting protocols and evaluationprotocols. A non-transitory computer-readable medium is provided in thecontrol module that is configured for storing one or more instructionsconfigured to be executed as part of a treatment protocol by at leastone processor of the system, which can be at least one processor of anelectrical stimulation device 50 or a user/physician controller 70, or aremote physician computer 70′ that communicates over the internet withrest of the system. These protocols may enable the control module 52 ofthe device 50 to responsively adjust its operation in relation to, forexample, the evaluation of sensed data (e.g. accelerometer data) ordetection of defined events as provided by the sensing module 55,patient input data managed by the user interface module 80, timeintervals assessed by the control module 52, and other triggers that cancause the selection, provision, and adjustment of therapy as defined bythe parameter values and algorithms related to a particular treatmentprotocol. The device 50 can also simply provide stimulation in responseto user input when operated by a user.

The control module 52 has a timing module 56 including a real time clockand a timer, a processing module 58 including at least one processor foroperating software, and processing information and parameter settingsthat are stored in memory module 60 and which allow for control ofdevice 50 operation. The real time clock can be used to calculate datesand time to provide event logging and to provide operations related tothe compliance module 200. The current date and time can be compared tothe date and time of the last stimulation that was provided and thepatient can be alerted if a selected amount of time has passedindicating that a treatment is due or has been missed. The time and datecan also be used to define and/or realize interval rules whichdetermine, for example, the minimum interval that must occur betweensubsequent stimulation periods. The date and time can also be used bythe payments and permission module 202 to determine if the device isstill operating within an interval allowed in relation to payment. Thestimulation module 54 can control at least one waveform generator/signalprocessor such as simulation module 62 that contains circuitry forgenerating pulses or arbitrary waveforms for output includingalternating current (AC) and/or direct current (DC) signals to be usedby one or more electrical, magnetic, optical, sonic, ultrasonic or othertypes of stimulus transducers.

The sensing module 55, may be realized as part of the AD/DA module 64when AD/DA circuitry (including AC-to-DC, DC-to-AC, and DC-to-DCconverters, and allows for both signal generation and acquisition. Thesensing module 55 contains circuitry and protocols for conditioning andanalyzing sensed data and can also for providing power to, and/orcommunicating with, various sensors including, for example, position,acceleration, electrical, EMG, optical, sonic, and other sensors thatmay be used by the system. The processing module 58 enables theassessment of sensed data and can provide detection of events that aredefined to cause delivery or adjustment of stimulation. Responsivestimulation may occur in a closed loop manner, via rules or controllaws, or may cause information (information about the sensed data) orsignals (a flashing light) to be presented to a user of the device 50,such as by an external patient device 72 or physician programmer 70, inorder to prompt provision or adjustment of therapy. The processingmodule 58 may be configured to store data in memory 60 such ashistorical sensed data records in order to track patient data, orassessment of sensed data along with usage and compliance data.

An AD/DA module 64 allows for conversion of input and output signals aswell as amplification, digital signal processing, filtering,conditioning, and also contains safety and regulation circuitry toensure patient and device safety. The AD/DA module 64 may also containcircuitry for multiplexing signals across different sensors orstimulators, and can contain switches and controllers for routing andcontrolling electronics of the system.

The apparatus 50 also includes a communication module 68 for providingwired and/or wireless communication with other system components (e.g.RFID identification to communicate between system components) such as auser/physician programmer 70 or management computer 71. Thecommunication module 68 can communicate with a computer at remotemedical facility 70′ (to allow data communication and programming tooccur remotely) either directly or by way of the user/physicianprogrammer 70. The communication module 68 can provide signals totransceivers which provide one-way or two-way communication of wirelesspower and/or data signals to implantable components such asneurostimulators. All wired or wireless communication can be realized atleast partially using the internet, or a local area network,Communication may also include means for magnetic, radiofrequency (RF),optical, sonic, and/or other modes of data and power communication withother devices. The communication module 68 may include circuitry,hardware, and protocols for providing WiFi, Bluetooth, cellular,magnetic, magnetic inductance, microwave, RF, electrical, optical,sonic, RFID, or other types of communication usingcommunication/interface ports 82, 144. For example, the ports 82, 144may connect to a system component which provides for wirelesscommunication of data or power signals.

The communication module 68 is configured for use with USB connectors(e.g. 83 c) and the like which may be provided as part of a userinterface panel 82. The communication module 68 of the device 50, aswell as communication circuitry may operate to send or receive signalsusing near field, far field, induction, magnetic resonant inductioncomponents, coils (e.g. an inductive coil assembly for powering animplantable device), antennae, and/or rectennae, optical sensors andstimulators, sonic stimulators and sensors, etc. This allows forsuccessful communication of identification, data or power signalsbetween any external and internal components of a particular embodimentof the invention. The apparatus 50 also has a power supply/rechargemodule 74 which can include components such as a battery, AC and DCconverters, diodes that function to rectify wireless power signalsharnessed by rectennae and circuitry related to the conversion orprovision of power which may be related to harvesting or transmission ofwireless signals, and can include a power cord for connecting to a wiredpower source through at least one of the communication/interface portsof panel 82.

The interface ports 83 may be connected to communicate with and/or powervarious sensors, such as sensors that are configured to measure bladderactivity, bladder pressure, bladder fullness, foot twitch, or othercharacteristic related to a condition or disorder being treated. In anembodiment, urodynamic measurements can be assessed before and afterstimulation to determine the effectiveness of a given set of stimulationparameters.

A signal routing module 63 provides components and switches that operateto route signals between components and modules of at least oneneurostimulator 50. For example, when a TENS protocol is selected themodule 63 may route the stimulation signals to a first connector 22 onthe housing of the device 50, while when a percutaneous signal is usedthen this is routed to a second connector of the device 50. Signalrouting may also be used when two or more stimulation targets arestimulated in order to route the signals to the appropriate set ofneedle electrodes or TENS stimulators. Signal routing may also be usedto send signals to a subset of TENs electrodes.

The I/O interface module 75 can contain circuitry and protocols forrouting signals and controlling communication related to various inputand output ports such as USB or other ports and can further containsafety circuitry and regulators that protect the patient and device 50from other devices that may be connected to the neurostimulator 50.

The communication module 68 can cooperate with the user interface module76 which contains hardware and software for presenting information to auser (e.g. patient or physician) and obtaining information/input fromthe user. Although the device 50 may communicate with a physician orpatient programmer 70, or external patient device 72, such as may berealized by a specialized device, smartphone or tablet computer, thedevice 50 may also have at least one signaling module 78 (which can bepart of the alerting module 204) with related circuitry and control adisplay 79 for presenting visual data in both text and graphical format.This may also be used to present a user with visual alarms related tothe provision of therapy and/or to operate a speaker 38 for presentingauditory signals such as instructions to patients related to the therapy(e.g., an instruction may inform a patient that a TENS pad may need tobe reapplied because the impedance value is too high). The signalingmodule 78 can have a Bluetooth enabled sound system that communicateswith a speaker 38, or sound transducer such as a hearing aid by way ofthe communication module 68. The device 50 can also contain patientinterface module 80 that permits operation of, and includes, controlssuch as a keyboard, nobs, switches, etc. to allow a user to provideinput. Input can be confirmed by an “enter” button 19. The interfacemodule may also provide for a menu guided system that allows foradjustment of device operation. It is obvious that various modules suchas modules 78, 79, and 80 can also be realized within the physician orpatient programmer 70,70′.

Both the control module 52 and the waveform generator module 62 may beconfigured with safety hardware and software routines, and can operatein combination with calibration routines of a calibration module 61 tocalibrate the apparatus 50 and to ensure proper functioning Inembodiments, the control module 52 allows stimulation programs to beimplemented according to protocols stored in the device memory andaccording parameters that can be adjusted by a user's manual inputobtained by the patient interface module 80. The safety routines of thesafety module 208 may limit the adjustments made by a user to rangesthat are safe.

The interface port panel 82 allows for connection to various systemcomponents. The device 50 may use at least a first stimulator conduit84, a second stimulator conduit 86, to communicate signals to a firststimulator 28 b and second stimulator 88. Conduits can comprise singleor multi-stranded electrically conductive, insulated electrode leadwires. The first conduit 84 has a first end connector that may contain aplug that electrically couples to a first stimulator interface port 83 aof the interface 82. When the device 50 is used to provide stimulationusing non-TENS modalities the third stimulator interface port 83 c maybe configured to be connected to a TMS device to control the provisionof magnetic stimulation as part of the system and method of the currentinvention.

Alternatively, the wired interface port 83 c can allow for connection tosensor components. When the stimulators are TENS electrodes, then thesecan serve as both stimulator and sensor, typically at different momentsin time. Stimulation electrode 88 can serve as sensor when the sensingmodule (or impedance module) rather than stimulation module isoperationally connected to a specific port during a selected period.However, other types of sensors may also be used.

In embodiment the interface port panel 82 may only consist of 1 or twoconnections that are distributed on the device housing. For example, theneurostimulator 50 can be realized in the form factor shown byneurostimulator 51 a and utilizes a transcutaneous electrode pad such asthose commonly used to provide TENS, which may have bottom surface thatis an adhesive and conductive surface (for attachment to a patient) anda top surface configured with connector 89 a which may be realized as anadaptor such as a metallic snap to be connected and disconnected to aconnector either on the bottom surface of the housing of theneurostimulator 51 a, or to connect to the end of a lead set. Theneurostimulator 51 a may have a lead set 86 containing a single leadwire for electrically connecting a single needle electrode 28 b or TENSelectrode 88, to the neurostimulator via connector 22. Alternatively,the lead set 86 can contain multiple lead wires for electricallyconnecting one or two percutaneous needle electrodes, and a TENS pad tothe neurostimulator via connector 22.

The alerting module 204 provides functions related to patient alertingand can include providing alerts using sounds emitted by a speaker 38 orvisual alert signals provided by displays 79 or communication signalssent using the communication module 68.

The impedance module 206 can provide operations related to ensuring thatimpedances of the leads used during stimulation are below a thresholdlevel and can provide a user with an alert if the impedance is abovethis level. This may be important for home users because stimulationwill not be effective if the TENS pads do not have good contact with thepatient's skin and they may not be well trained to notice bad skincontact.

The patient safety module 208 can provide operations and controlhardware related to ensuring patient safety. For example, if the moduleassesses that a calibration or maintenance date stored in the module haspassed it may set a flag and provide a message to a user or may notallow device operation until the flag is reset when the indicatedoperation is provided. The safety module may also not permit certainoperations such as providing patient treatment when the device 50 isconnected to a recharging power source.

Payments and Permissions

The payments and permissions module 202 provides for management ofdevice operation. This can include setting what operations and valuesare permitted to be accessed by a user. Passwords may be required inorder to grant access. The module 202 also can allow a user to provideinformation related to using and purchasing of treatment credits. Thiscan include medical billing information, reimbursement codes, creditcard account numbers, user or clinic information and other informationrelated to payments or treatment credits. For example, submission ofcurrent procedural terminology “CPT” codes can allow for appropriatecoding of the diagnosis using ICD-9 code as determined by the Centersfor Medicare and Medicaid Services (CMS) and relate to determination ofassociated fees for providing stimulation. The reimbursement codes caninclude whether SAFN or PTN targets are being used and can also indicateif the stimulation protocol being used is for one leg or for both legs.Reimbursement codes used by the system 10 may be country or regionspecific. Additionally, the payments and permissions can be modifiedaccording to region or state. For example, certain states may covercosts related to certain types of stimulation protocols while otherstates may not and so the operation provided by the system 10 or thetype or amount of a charge associated with a particular treatment creditmay be adjusted accordingly. Information related to a patient or apatient's insurance may also be used in the processing of the treatmentcredit information. This can allow the cost for severe or moderatepatients, who may need more stimulation sessions, to pay the same amountas patients who need less.

In an embodiment, a neurostimulator 51 a is preferably configured tocommunicate with a computer system 71 which provides a treatment creditpurchasing system and also allows for monitoring the status and usage ofa neurostimulator. For example, the neurostimulator 51 a can communicatewith the computer system wirelessly or through an input/output connector144 a which may be realized as a universal serial bus (USB) connector.Information can also be provided to the neurostimulator 51 a using aportable digital storage device such as a USB flash drive. The USB flashdrive may allow two way data exchange between the computer system andthe neurostimulator or may only be used to update information in theneurostimulator.

If wireless communication not available near a user of aneurostimulator, a user is not technically savvy, or if there are otherreasons (e.g. regulatory) why a neurostimulator may not be provided withwireless connectivity, it may be advantageous to provide a physical key,such as a USB memory key. The key may programmed and can be read by theneurostimulator to provide a selected number of treatment credits, or toallow the neurostimulator to operate for a selected amount of time oruntil a specific date. The USB memory key may fit into an I/O port 144of the neurostimulator, which can then read the USB key and update itsinternal parameters. In an embodiment the USB key may be required to beattached to the neurostimulator during use. The USB key and theneurostimulator may be matched 1-to-1, via the payments and permissionmodule 202 which may be programmed to only read a USB key having aparticular ID code: the USB key can only be used with a particularneurostimulator. A patient can receive a USB key in the mail and canmail back a previously sent USB key. Alternatively, a patient can bemailed a code that can be manually input by a patient to re-activate theneurostimulator for a duration or to provide additional treatmentcredits, according to a prescription or otherwise. Alternatively, asmartphone running specialized application software can communicate witha remote computer 71 and the neurostimulator 51 a to manage treatmentcredits. This allows the neurostimulator to remain relatively simple,and the circuitry and hardware of the smartphone may be relied upon.

In embodiments the neurostimulator 51 a includes a control system 52with a microcontroller/processor 58 which operates the payments andpermission module 202 to manage and store information relating topayment credit status, historical usage, compliance data, and otherparameter values of the neurostimulator 51 a. The payment status andusage information may be transferred between the neurostimulator 51 aand the computer system 71 when the neurostimulator is in communicationwith the computer system 71. The control system 52 monitors the value ofa treatment credit counter which indicates a treatment credit valueassociated with the number of treatment credits that are available.

A treatment credit can correspond to allowing for various types oftherapy provision. For example, a treatment credit can be set equal to atreatment session of, for example, 30 minutes of continuous stimulation,and after a treatment session is completed, the number of availabletreatment credits is decreased by 1. Further, a therapy session may haveto be interrupted or paused. Accordingly, in an embodiment a treatmentsession can have a minimum duration defined before a treatment credit isused, such as 15 minutes. The treatment sessions can also be defined asa selected interval of total provided stimulation (e.g. 30 minutes). Theinterval may be allowed to occur within a selected interval (2 hours).This can allow for 1 or more interruptions or pauses to occur duringtreatment. If there are no more treatment credits available to theneurostimulator 51 a, then the processor 58 operates in a manner thatprevents the neurostimulator 51 a from providing a session of treatment.For example, this can be done by preventing operation of the stimulationmodule 54 and also presenting a user with a message or alert using thealerting module 204. In this case, additional treatment credits can bepurchased and uploaded into the neurostimulator 51 a to allow forsubsequent treatment sessions to occur.

If the neurostimulator 51 a is not used during an interval defined fortreatment, or is used less than a minimum selected amount (e.g. 15minutes) then the payment and permission module 202 of theneurostimulator 51 a can automatically increase the stimulation-creditvalue by 1 to the prior value. When multiple patients are treated by theneurostimulator the physician can enter the patient ID into either aphysician computer or the neurostimulator so that a particular patientis associated with the stimulation session.

In an embodiment, the neurostimulator is permitted to providestimulation therapy-sessions while the treatment credit value is zero ornegative, as long as the stimulation credit value of the neurostimulatoris above a defined payment threshold such as −50 units. Further, atreatment credit rule can be implemented by the payments and permissionsmodule 202 of the neurostimulator 51 a, whereby the negative valuereflecting a treatment credit deficit must have lasted less than aselected interval such as 90 days. This feature can be important forsome clinical practices since a clinic may not be paid or reimbursed fora treatment session until several weeks or months after a treatment isprovided to a patient. In this manner, a clinic does not have to pay inadvance for credits that may not be used for some indeterminate time inthe future.

For various disorders or treatment regimens, a session-based stimulationparadigm may not provide an appropriate unit of therapy. For somepatients and disorders more than one session will occur during aparticular day. For example, when the neurostimulator 51 a is used forproviding treatment related to pain, migraine, headache, sleep apnea,etc., rather than for treatment of overactive bladder, then severaltreatment sessions can be needed to relieve symptoms. The patient and/orclinic should not be required to use multiple treatment credits. If atreatment credit allows providing only a single session that occurs fora particular day then problem occur. Some patients may worry about costand try to use less treatment credits rather than providing themselveswith additional needed therapy.

Accordingly, in embodiments each treatment credit can enable therapy tobe provided multiple times across a selected interval such as a singleday, week, or other defined period. Further, the neurostimulator paymentand permission module 202 may be configured so that a maximum number(e.g., 10) treatment credits can delivered to a neurostimulator 51 a ata particular time. This provides for an advantage that a patient mustcontact a doctor or service provider after a period of, for example, twomonths. Further, although at least one treatment credit is available,the payment and permission module 202 of the neurostimulator 51 a maynot allow therapy to be provided in selected circumstances. This mayoccur if a compliance criterion is not met or, for reasons related topatient safety, a certain number of stimulation sessions, or totalstimulation time, may only be allowed to occur within a selectedinterval such as 1 day.

FIG. 9 shows a block diagram of circuitry modules provided in anembodiment of the neurostimulator 51 a. An graphic display 20 such as anLCD visually presents information related to operation such asneurostimulation parameter values or information about compliance asshown in FIGS. 7A,7B, power levels, elapsed time of stimulation, andtreatment credit information. Patient input control can be realizedusing buttons such as power button 14, dedicated buttons 16 (e.g.,start/pause/assess button), navigation controls 18 to assist a user incontrolling the operation of device 51 a via theprocessor/microcontroller 58 of the control module 52. The “assess”button allows the assessment of different stimulation parameters such asamplitude prior to providing therapy. The processor 58 controlsoperation the stimulation module 54 which includes a high voltage supply(DC to DC converter 154), pulse generating circuitry 140 and presentsvalues of related operational characteristics on the display 20 usingcontrol circuitry of the control module 52 including a set ofcontrollers 148. The pulse generating circuitry 140 can also providecircuitry that cooperates with the lead set in order to blow a fuseafter the provision of simulation as is done in commercial systems thatutilize single use paradigms. The controllers 148 can act as sets of oneor more switches or be otherwise realized to adjust and control theoperation of components of the stimulation module 54 including, forexample, a DC to DC converter module 154,digital-to-analog/analog-to-digital converters 152 under control of theDA/AD circuitry module 64. The controllers 148 can also act as sets ofone or more switches or be otherwise realized to adjust and control theoperation of the sensing module 56 in order to provide sensing at one ormore sensors. The stimulation module also communicates with the wirelessmodule 210 in order to provide power and/or data wirelessly tocomponents of the system 8, such as an implantable neurostimulator ordirectly to human target tissue as may occur in TMS treatment fordisorders such as depression, migraine or headache. One or more alertingcomponents 156 may include a vibrating buzzer, speaker, light emittingdiodes, etc. may be provided for notifying a user or patient aboutinformation relevant to therapy. This can include an indication, forexample, that a treatment session is completed or is scheduled to occur,an impedance value is above a selected amount, a time has elapsed, thepower has fallen below a selected amount, or other problem has occurredwith the neurostimulator 51 a.

In an embodiment, at least one port 144 enables communication to occurby way of the communication module 68 between the device and othercomponents of the neurostimulation system 10 such as a USB, micro USB,or conductive cable connects to an I/O interface 168 module that canhave isolation electronics such as an isolator 158 and isolated DC-to-DCconverter 160 in order to electrically isolate at least one of the I/Oports 144 a,144 b from the other circuitry and components of theneurostimulation system 8. The neurostimulator 51 a can also include apower management/charging module 74 with a power management circuitry toregulate power operations. The power management /charging module 74 caninclude, and be disposed between, a battery 142 and the processor 58.The power management module 74 can have components to charge the battery142, such as a wireless power harvester (e.g. induction coil configuredfor receiving energy by magnetic induction or rectennae configured forreceiving RF or microwave energy) and associated circuitry, and/or canbe configured for recharging the battery 142, using power from an I/Oport 144 b. One or more fuses can provide for both patient and devicesafety, such as fuse 164 disposed between the battery 142 and processor58, or battery 142 and the other components of the powermanagement/charging module 74. Regulators can be provided such asregulator 166 for maintaining a constant supply voltage to the I/Ointerface 168 when I/O ports 144 a and/or 144 b are connected toexternal equipment. Although shown as portable devices, theneurostimulators shown herein may be configured to be recharged usingpower converter that is plugged into a wall socket, with appropriatesafety.

FIG. 10A, shows a menu screen of a computer system such as a computer ina medical clinic that is connected to the internet. In an embodimentrelated to use of neurostimulators 51 a in a clinic, the computer mayserve as a user/physician programmer 70. The menu screen 170 is a userinterface and includes virtual buttons that allow selection ofoperations related to managing one or more neurostimulators 51 a. Eachvirtual button of the menu screen 170 can be supported by acorresponding module which includes all software and hardware requiredfor implementing related tasks. For example, the manage treatmentcredits button 172 a is part of a module that allows for purchasingtreatment credits to be used with a particular neurostimulator 51 a, andcan operate with the payments and permissions module 202 of the system.

The user of the menu screen 170 may be a patient, doctor, technician,health care professional, office employee (with sufficient permissions),or anyone that manages treatment sessions with patients. The menu screenserves as a user interface that allows for user input and may beconfigured differently for different users. Pop-up dialogue boxes withfields for user ID and passwords can be presented to a user for makingcertain selections or adjustments. Clinics staff can enter ID codesassigned to the clinic in order to modify, view, and selectively adjustvalues related to a patient account, including managing payment credits,patient customer's account and related to programming and/or settingoperating parameters of a neurostimulator 51 a. The menu screen 170 isaccessible from web-based application using a physician programmer 70 orcomputer.

A screen component shows status settings 174 related to one or moredevices being adjusted by a user operating the menu, including deviceidentification and use/connection status.

A button control, and associated module, is shown for managing treatmentcredits 172 a. This selection invokes additional screens for managingand purchasing treatment credits, requesting treatment credit refunds,and for viewing a history of treatment credit transactions. It can alsoinclude dates and times of treatment credit purchase, download, therapyprovision, patient ID and reimbursement code information, and otherinformation. In an embodiment, a treatment credit can contain datafields having information about characteristics of the therapy to beprovided such as the maximum treatment session duration, or can containan interval or date during which the stimulation may be provided.Treatment credits may be provided with an expiration date after whichthey can no longer be used and become “expired”. These may be exchangedfor new treatment credits or “refreshed” using the module.

A button control, and associated module, is shown forrefreshing/restoring 172 b which will update the values on the statusscreen 174 to reflect for example, the current number of treatmentcredits for one or more neurostimulators 51 a. The selection can alsoprovide screens with options to, for example, restore a device to itsdefault values, clear device memory, etc.

Additional selections that are provided include a button control, andassociated modules, for adjusting account information related to aclinic or patient 172 c.

Additional selections that are provided include a button control, andassociated modules, for providing technical support such as viewingmanuals or instructions on how to operate the device, or providing achat window with a customer service representative 172 d.

An additional selection that is provided is a button control, andassociated module, for performing a calibration or diagnostic routineand displaying the results including whether the device passed varioustests 172 e. The selection can allow for running diagnostics such as adiagnostic check on a device 51 b using a USB or other cable (loop-backcable), or by sending instructions and receiving data related tocalibration and system test results wirelessly and if necessaryrequesting technical support 172 d.

An additional selection that is provided is a button control, andassociated module, for managing or requesting reimbursement fortreatment by a patient's insurance company 172 f.

An additional selection that is provided is a button control, andassociated module, for viewing usage and compliance 172 g. This permitsobtaining, viewing, and managing historical data records related tousage, and further presented in relation to compliance criteria. Menuscreens invoked when this button is selected can provide for a graphicalor table view of the usage of one or more neurostimulators 51 b. Thiscan include information on patient ID, number and ID of associatedtreatment credits and reimbursement codes and payment informationassociated with the credits. This can include screens of patient usageas shown in FIGS. 7a and 7b . This can also include screens that allowfor programming of compliance criteria such as weekly treatment goals aswell as what to do in the case that criteria are met or fail to be met.Options related to how, when, and what information is queried of thepatient (e.g., about symptoms, medication compliance), and schedulingpresentation of survey items is also provided.

A button control, and associated module, is shown for allowing a user toadjust or run a treatment session 172 h using an invoked menu interfaceto select or adjust a stimulation program and control theneurostimulator 51 a to provide treatment. The treatment module 172 hand control module of the neurostimulator may both containnon-transitory machine-readable storage media configured to storemachine-executable instructions that is executed by processors of thesystem and can also include, for example, a look-up table, formulas,algorithms, a database having a matrix of treatment protocols and valuesassociated with the protocols. For example, each column associated witha particular treatment contains parameter value settings such asfrequency, amplitude, duration, duration of therapy, stimulator at whichthe signal is applied, inter-therapy intervals during which stimulationis not provided, number of maximum treatments allowed per day, number oftotal time allowed per day, maximum stimulation strength allowed, andany other operational parameter related to treatment withneurostimulator that is external or implanted.

An additional selection is an “Administrative” button control 172 i, andassociated module, for providing administrative operations which invokesadditional screens that allow for changing passwords and/or user IDs,for defining allowed ranges for stimulation parameters, for registeringa neurostimulator to a particular patient (which can include options forviewing and modifying device information of the neurostimulator 51 a).

An additional selection is a “Login/logout” button control 172 j, andassociated module, for allowing the device 51 b, user/physicianprogrammer 70, or remote user/physician programmer 70′, to establish andterminate communication with each other or with the Management Computer71.

FIG. 10B, shows an embodiment of a menu screen of a computer systemdevice of the system 10, which can be used for setting usage andcompliance parameters. Usage parameter values 176 can be set for maximumand minimum amplitudes used during stimulation as well as the number ofleads at which stimulation is provided (which may be allowed pertreatment credit) and the frequency at which stimulation occurs.Additionally parameters may include inter-stimulation pauses duringwhich stimulation is not provided, ramping up or ramping down intervalswhich allow for smoother therapy onset and offset in order to deterdisturbing a sleeping subject, maximum duration or # stimulationsallowed for a given interval “dose”, and any of the other stimulationparameter settings or limitations disclosed herein. Settings related tocompliance 178 can be adjusted including, for example, number of daysper week that stimulation should occur during the day (and the minimumand maximum time for each session). In this example, since the maximumamount of time is 2 hours the device may be set to not allow stimulationto occur longer than 2 hours in any particular 24 hour period if a“number of sessions per day” is set to 1. Compliance can also be set forthe number of nights per week that stimulation should occur (and theminimum and maximum time for each session—in this example there is nomaximum time limit). Compliance restrictions may also be related todose-based criteria, for example, a higher amplitude stimulation signalcan be associated with a shorter allowable interval (or total duration“on” over a selected interval) so that the “dose” remains approximatelysimilar. Dose-based compliance relationships can be linear, such asdoubling the stimulation amplitude (or number of pulses provided by aTMS coil) which can result in a halving of the maximum allowableduration or number of stimulation sessions allowed per unit time.Alternatively, strength/duration dose relationships may be non-linearand non-proportional. For example, in the treatment of depression, ifthe neurostimulator includes a TMS coil that delivers “N” pulses of “S”strength, and the user increases the number of pulses to 3N, then S maybe reduced to 90%. The strength/duration, strength/number of treatmentsper unit time, or strength/number of stimulators used to providestimulation, relationships defined by compliance criteria or otherrestrictions related to the provision of stimulation (e.g., defined inthe payments and permissions module) may be defined in various manners.It may be defined by a prescription of a patient that is written by adoctor and realized in electronic form by the system, by findings of asafety study, by the severity of a disorder, by patient response totherapy, according to answers of survey questions, according toimprovement seen during therapy, by drugs taken concurrently as part oftreatment, by the patient's measured tolerance for pain, or otherwiseand may be stored in a look-up table or defined by an equation of theset compliance module 178 which works with the compliance module 200 andother modules of the system.

The treatment session credit field shows that there are 60 treatmentcredits remaining prior to the device no longer allowing the user toprovide stimulation sessions. Also a selection has been made toconfigure the system to cause a decrement of one treatment credit eachday that the user provides at least one stimulation session. If“session” had been selected then each time the user provided astimulation session lasting longer than a selected amount (e.g. 5-30minutes) then the treatment credit value would be decremented by 1. Ifthe user stops before a minimum time limit (e.g., 5 minutes), then thesession may not count and the treatment credit is not adjusted. Anactivation interval is also shown and the value is 90 days. Thisindicates that the neurostimulator will remain activated for 90 daysfrom the current date. The treatment credit or activation intervalfields may contain values or be left blank. If an interval of activationlimitation is used without a treatment credit limitation, then thedevice will continue to provide stimulation treatment until the end ofthe interval. In an embodiment, in the case where no maximum is definedfor the day/night stimulation fields (e.g. currently set at 3 and 3,where “3+” would signify “at least 3”) then the user would be allowed touse the stimulator as many days as desired before the expiration datedefined by the 90 day interval. There may also be compliance rules setup combination rules that utilize “if”, “and”, and “not” logic, such asa rule which does not allow stimulation to occur during the day ifstimulation was provided the preceding night. In embodiments, the system10 or neurostimulator 51 may be required to check (either periodicallyor before each use) for an active prescription (in a wired or wirelessmanner) in order to ensure that a doctor intends stimulation to beavailable. Like the treatment credit information, the prescription datastored in a computer 71,70′can also set limits for the maximum number,or length, of stimulation sessions per day. The current settings can becompared to the prescription if the “check prescription” value is set to“Y”, which sets an operational flag in the payments and permissionsmodule 202.

An “Alerting” button control 172 k, and associated module, allows forsetting alerting parameter for system components including device 51 b,user/physician programmer 70, remote user/physician programmer 70, canalso be used to alert a patient's smartphone, a customized EXD-pagertype device worn by the patient, or remote Management Computer at aremote site 71 to send an alert (e.g., via e-mail or text message) to apatient to alert to various events including an upcoming therapysession, or to remind a patient if the therapy session was missed.

A “Non-Compliance” button control 172 l, and associated module, allowssetting parameter values and operations that contingently occur due tovarious types and thresholds of non-compliance. For example, alertingmay also be set up to send an alert from the user programmer 70 to aclinic's computer 70′ if the patient is severely non-compliant anddevice usage data meets a non-compliance threshold criterion establishedfor the compliance module 200, for example, the data shows a failure toprovide any therapy over the span of a month.

Another selection that is provided is a “QOL/Diary” button control 172m, and associated module, for allowing setting of operations related toobtaining quality of life (QOL) data and/or bladder diary data. Forexample, survey items for an electronic bladder diary may be presentedto a patient on a defined schedule such as once a week. The data may beprocessed in different manners such as being used to generate summarystatistics and trend graphs related to symptom improvement over time.The QOL/Diary/symptom data may be transmitted with other data to acomputer in a clinic 70′ so that this can be reviewed by a doctor priorto, during, or after a patient's clinic visit. The bladder diary itemsmay be presented to a user visually in textual format with graphicswhere appropriate, or can be presented through a speaker of a deviceusing text-to-voice technology or using pre-recorded messages. Userresponse can be obtained by a user interacting with the neurostimulatoror patient programmer 70 to select a score (e.g. choosing between 1 and7, on a 7 point likert scale), or by voice, if the device is configuredwith voice-to-text recognition. A user's responses can simply bedigitally recorded and analyzed at a later time by a transcriberservice. The non-compliance criterion can also be defined for theprovision of QOL, bladder diary, or other survey responses data. Userresponse data can occur across 1 or more scheduled sessions. AlthoughQOL and bladder diary information are used in this example, theneurostimulator 51 a can be configured to provide any type of assessmentinstrument or survey items related to a disorder suffered by, orcondition to be modified in, a patient. This may include the assessmentof depression, migraine, memory, pain, sleep apnea, anxiety,hypertension, tremor, concentration/attention/focus, reaction time, etc.

A “Send to Device” button control 172 n, and associated module, allowsthe user to update the neurostimulator 51 a and/or the programmer 70with the new settings.

A “Send to Memory stick” button control 172 o, and associated module,allows the system to enable the updating of the neurostimulator 51 a byproviding the information on a memory stick that is given to thepatient. When a patient does not want to visit a doctor's clinic anddoes not have access to internet or cellular coverage, or who may not becomfortable operating a computer, a memory stick may be provided whichcan simply be plugged into an I/O port 114 of a device 51 a. This willprovide an update to the device data and allow for continued treatmentof a patient. Routines a communication module 68 can allow upload of alldevice information (including usage and compliance) to the memory stick.This can then be sent back to the doctor's office so device data can bereviewed.

A “Generate Code/Tones” button control 172 o, and associated module,allow for a code to be generated which can be printed out and sent(mailed/e-mailed) to a patient who can then enter the code into theneurostimulator 51 a or programmer 70 using the user interface module 76in order to allow for continued treatment of the patient. The code mayextend the duration during which the device may be used, or increase thenumber of treatment credits which are present in the device. Inembodiments, instead of a code, a barcode or the like (Data Matrix andQR Codes) can be printed out and the programmer 70 can read the code viaa digital camera in order to re-activate the device. In embodiments, acomputer can use a sonic protocol as is done by facsimile machines cocommunicate with a device 51 a over a phone line, with appropriatemodulation, handshaking, and demodulation implemented within thetransmission protocol.

In an embodiment, operation of the menu screens shown in FIGS. 10A and10B displayed to a user by a computer system, allows patient selectionsthat cause a first processor of the control module 52 of theuser/physician computer 70 to transmit data signals to a secondprocessor of a remote computer 70′ (or 71) which has been configuredwith communication 68 and control 52 modules designed to receive andoperate upon the information data sent from the first processor.Further, the second processor is configured to access information valuesstored in memory 60 such as in at least one table that can be related totreatment of a patient such as: parameter values for a stimulationprogram, treatment credits, activation interval during which the device51 a is permitted to operate, values related to a status or limitationsof a prescription of a patient, compliance data and/or criteria of apatient, payment information of a patient, insurance information of apatient, payment and identification information of a clinic, rights andprivilege information that is related to a user of a neurostimulator,maintenance information related to a neurostimulator, and/or geographiclocation information related to a neurostimulator if the neurostimulator(or other system component) has GPS or uses other geo-locationtechnology.

The information can be operated upon by the processor of the remotecomputer according to algorithms and rules related to compliance,payment, and provision of stimulation therapy by at least oneneurostimulator 51 a. The second computer can then transmit the resultdata of this processing as result information data to the physiciancomputer 70 in order to select, update, adjust, allow, disallow, orotherwise operate upon the settings that effect operations of aneurostimulator 51 a in a manner that adjusts the provision of therapyfor at least one patient. As is the case for the patient programmer 70and other components of the subject invention, the components shown inFIGS. 10A and 10B can be used for stimulation systems which incorporateTENS and percutaneous stimulators as well as those having fully orpartially implantable stimulators, and systems using implantablestimulators powered by external components. Combination systems can alsobe supported, such as providing TENS from an externally worn controllerwhich also provides power to an implanted neurostimulator.

During a communication session when the neurostimulator 51 acommunicates with the computer 70, a processor can cause information tobe updated and stored in the memory of the neurostimulator 51 a. Thiscan occur contingently based on user input operating the menu the menuscreen 170. For example, if one or more treatment credits are purchased,or are otherwise renewed (e.g., based upon the user meeting compliancecriteria), then the treatment credits are sent by the computer 70 andreceived by the neurostimulator 51 a processor and the number ofavailable treatment credits is updated in the payment and permissionmodule 202 in order to enable treatment sessions to occur. When theneurostimulator 51 a is in communication with the computer 70 or acomputer system network that communicates, in a wired or wirelessmanner, with the computer 70 then parameter values used by theneurostimulator 51 a during operation (e.g. a permitted range of valuesfor various parameter settings) can be adjusted.

TENS System and Method Embodiments

Although the SAFN or PTN may be stimulated using generic TENSstimulators having at least a first and second TENS electrode that canbe placed to provide stimulation of these nerves, recent TENS technologyhas moved towards specialized systems which are wireless and which usepads or electrode arrays and also provide features which promote bettertreatment response and easier patient experience. FIG. 11A shows anembodiment of a system for providing SAFN TENS stimulation of a patient6 which includes at least two adhesive TENS pad electrodes 30 e, 30 fthat are disposed within a leg applicator accessory 220 which may be agarment configured for positioning at least one electrode on the medialupper calf area. The garment maybe a customized sock, wrap, or similartype of shaped garment that can be worn by a user. In this embodimentleg applicator accessory 220 serves to position at least two TENSstimulators within the material and along the medial leg surface withthe first positioned approximately several inches below the knee and thesecond located about midway between the first electrode and the medialmalleolus. Although the accessory 220 is shown here forming a sock, theaccessory 220 can be designed extend distally only to a locationcephalad to the medial malleolus and does not need to cover the foot. Alead set 86 c can travel within the garment or be routed along hegarment and communicates the stimulation signals to the electrodes 30 e,30 f from a neurostimulator 50 (not shown), which may be strapped to apatient's leg, worn around the patient's waist, or disposed in a pocketon the top of the accessory 220. The electrodes can operate in a bipolarmanner with electrodes 30 e, 30 f or these can both be referenced to anadditional electrode, which may be on the bottom side of theneurostimulator. Rather than both electrodes being below the knee, onecan be above and the other below as may occur with a knee sleeveelectrotherapy garment with dual electrodes. Typically, when aconductive fabric is used, this should be formed within the conductivegarment areas isolated so that stimulation can be applied to the SAFNwithout stimulating other targets such as calf muscle or the sural nerveon the lateral side of the leg. A shaped area of electro-conductivegarment 31 is shown around electrode 30 f.

FIG. 11B shows an alternative embodiment of a system for providing SAFNTENS stimulation of a patient 6 which includes at least two adhesiveTENS pad electrodes 30 g,h and 30 i,j (j is not shown) that are disposedwithin each of two upper leg applicator accessories 222 a, 222 b, madeof a formed and/or elastic garment material that can be worn by apatient and which serves to position the stimulators along the medialleg surface approximately at or below the knee to 3 or 4 inches belowthe knee (although in embodiments it may extend to just above the medialmalleolus). The stimulation provided by the embodiment in 11B may besuitable for stimulating the infrapatellar branch of the SAFN, which maybe less comfortable for some users and may also be more difficult toassess with respect to confirming correct placement of the electrodes. Alead set 86 d communicates the stimulation signals from aneurostimulator 51 c which here is shown disposed on the top of theaccessory 222 a (it can be configured to be snapped onto the garment orheld in pocket disposed in the garment), to the electrodes 30 g, 30 h.An electrode pad 30 i is shown on accessory 222 b which communicates toanother neurostimulator (not shown), in order to provide bilateralstimulation. Alternatively, all electrode pads can be connected to asingle neurostimulator using a wire that runs up one leg and down theother. When two neurostimulators are used, they may communicate in awired or wireless manner in order to synchronize the stimulation of bothlegs so that the signals applied to the first and second leg occur at adesired lag, which may be a delay of zero as set by the stimulationprotocol. When a 10 Hz stimulation signal is applied to each leg180-degrees out-of-phase, then the stimulation may project caudally at20 Hz at locations commonly innervated by the peripheral signals fromeach leg.

FIG. 11C shows an alternative embodiment of a system for providing SAFNTENS stimulation of a patient 6 which may be more simple because it doesnot have free-standing lead wires. The neurostimulator 51 d can berealized in a basic embodiment that has only a few controls and nowires. The neurostimulator 51 d has a first wing 224 a having a top sidewith a first control 16 a which is a plus symbol “+” and a second wing224 b having a top surface with a second control 16 b with a negativesymbol “−”. The neurostimulator 51 d components are contained within ahousing having a center region with a battery compartment 228 foraccepting at least one rechargeable or disposable battery 142 whichpowers the neurostimulator 51 d. The control module 52 of theneurostimulator 51 d is connected to the first and second user interfacecontrols 16 a, 16 b. The user can turn on the device 51 d, under controlof the control module 52 by pressing the user interface controlsaccording to defined patterns. For example, pressing the first andsecond button 16 a, 16 b for 3 seconds can turn the unit on and doingthis again will turn it off The user can increase the stimulation bypressing the first control 16 a or decrease the stimulation by pressingthe second control 16 b. In an embodiment, after the device is turned onand connected to a user to obtain sufficient impedance levels, it willprovide a timed stimulation session which lasts a selected interval suchas 30 minutes, after which the device may power down. Alternatively, thedevice may continue periodically (every 2 hours) provide additionalstimulation sessions (e.g., pulse rate 5 to 50 Hz and pulse width 150μs) as long as it remains connected to a user. The first and secondwings are made of a flexible material such as rubber or silicon and havesnap connectors 89 a, 89 b on their bottom surfaces (that receivestimulation signals by a lead set 86 e that resides within each of thefirst and second wings) which attach to an electrode array comprisingtwo electrodes provided as a reusable adhesive electrode pad that hasthe same shape as the device 51 d and which snaps onto the connectors 89a, 89 b of the first and second wings. Signal transducers for providingalert signaling 156 can include a led diode or speaker provided on thetop surface of the first wing in order to notify the user about thestart or stop of stimulation therapy and also can provide a warningalert if either electrode pad is not attached correctly as can bemeasured by an impedance module or other electronics that can detectthis problem. The unite can use codes such as “a single long high beep”or “two long high beeps” where high is 1000 Hz or a low buzz (500 Hz)if, for example, the power management 74 indicates that the battery 142is low. Voice messages can also be used. A communication module may alsobe provided to enable the stimulator 51 d to wirelessly send and receivedata and be controlled by a smartphone which can serve as auser/physician programmer 70. Additionally, diodes or an LCD can allowsignaling of information such as battery charge.

In order to maintain the neurostimulator 51 d in position at least afirst strap 229 a is provided which is attached to the first wing 224 aand configured to wrap around the calf area to secure the first wing theuser's leg. Additionally, a second strap 229 b may be provided which isattached to the second wing 224 b and configured to wrap around the calfarea to secure the second wing to the user's leg. The straps act tosecure the neurostimulator 51 d in position and bias each of the wingsand the TENS attached to the bottom surface of each wing against theuser's leg. A strap can also be configured to be attached to the housingof a neurostimulator or an electrode array rather than the two wings.The strap is configured with a length and fastening means which allowsfor the strap to wrap around a leg circumference of between 30 to 48 cmcorresponding to that expected in the calf area of an adult user(McDowell et al Anthropometric Reference Data for Children and Adults:United States, 2003-2006).

When the neurostimulator 51 d is configured to work jointly with animplantable neurostimulator which is controlled by an externalcontroller, then conduits 86 a may conduct energy to power either RF ormagnetic transmitters in order to power the implanted device.Alternatively, the RF or magnetic transmitters can be located in thehousing of the neurostimulator 51 d and the neurostimulator 51 d may beconfigured to also provide TENS either concurrently or at a differenttime than the implantable neurostimulator provides stimulation. Theneurostimulator 51 d can be controlled by a user programmer 70, whichmay also control the implantable neurostimulator either by communicatingdirectly or by working jointly with the neurostimulator 51 d.

FIG. 12 shows an embodiment of a method for performing OAB treatmentsuch as an SAFN stimulation treatment session using a neurostimulator 51a. Various steps may be performed in a different order, omitted, orrepeated. In a general embodiment the steps of FIG. 12 can occur so thatthe device is operated based upon a verification-treatment basis. Thismeans that when one or more defined verification criteria are met,stimulation treatment can be provided to a patient. The verificationstep can simply entail assessing if a per-treatment session paymentcredit is available, and if not then a payment must be made before theneurostimulator 51 a is “verified”. For example, during verification thenumber of stimulation-credits of the system 10 is assessed and must beabove a selected value for verification to be true. Once verified thedevice is granted permission (i.e., set a verification status flag totrue) to provide stimulation. The stimulation treatment credit value isdecremented by a value of 1 either in a device 51 a or in auser/programmer 70 before, during, or after the stimulation is provided.The permission flag may have a time limit such as a subsequent intervalof one hour, 2 hours, one week, or other defined interval. The decrementin treatment credit value may only occur after a stimulator 51 a hasbeen used for a minimum amount of time such as 7 minutes in order toavoid charging a user for an “incomplete” stimulation session that doesnot last a minimum duration. In step 230, a user (patient or physician)obtains a neurostimulator 51 a and performs the additional steps to setit up.

In step 232, a user establishes a user account on the computer system.If the neurostimulator 51 a has not been previously used by the userthen the user can link the neurostimulator 51 a with a user accountand/or user ID. The user ID may be for a clinic when the device is usedin a clinic or may be for a patient who will be treated by the clinic.The User ID can be for a user when the device will be used at apatient's home. Preferably, the payment and permission module 202 of aneurostimulator has, or is assigned, a unique identification number bywhich it is identified during communication/transaction with a computersystem.

In step 234, a user can sign into a user account, navigate to a menu 170and select, for example, a choice of “manage treatment credits” 172 athat enables the purchase of one or more treatment credits. Eachpurchased treatment credit that is uploaded to the physician programmer70, and/or the neurostimulator 51 a preferably includes data and aunique identification number.

In step 236, communication between a neurostimulator 51 a and a computersystem (which may include any of 70, 70′, 71 and communicationtherebetween) is established using wired or wireless communication.Communication can also occur between the computer and a memory stickwhich will then be used to transfer data and credits to theneurostimulator during a separate step. The modules can be stored andoperated on a server computer having a processor and control moduleconfigured to provide user accounts that can also allow management ofuser and device information. The communication can include readingand/or adjustment of initial parameter values that are set for thedevice 51 a at the start of the communication session and finalparameter values that exist at the end of the communication. Step 236can include a step of providing information to a user on a display 174of the physician programmer or on a display 79 of the neurostimulator 51a.

After verification that the neurostimulator 51 a is an authorized device238 that has been associated or “linked” with a particular user accountand/or user ID, in step 240 the computer system transmits one or moretreatment credits that are available or which may be purchased to theneurostimulator 51 a. Alternatively, as has been disclosed, informationcould be transferred between the computer system and the neurostimulator51 a using a digital storage device such as a flash drive as part ofstep 240. In step 240 a code can be generated that is simply manuallyentered or optically scanned into the neurostimulator 51 b by a user andoperation of the payments and permissions module 202 has been previouslyprogrammed to interpret the code to provide appropriate functionality.

Transmission of a purchased treatment credit between an externalcomputing device and the neurostimulator 51 a, can include one-way ortwo-way communication of information related to number of remainingtreatment credits available (if any), the total number of treatmentsessions (and associated times and intervals) which have already beenprovided, or which are scheduled to be provided by the neurostimulator51 a, a count, including details, related to “incomplete” treatmentsessions that did not last longer than a minimum amount (and relateddetails), information related to the use of a particular treatmentcredit based on a unique serial number and any associate informationrelated to a user account, user ID, patient ID, and other operationalinformation. Instead of treatment credits and especially in the casewhere a user of the neurostimulator is used by a patient rather than aphysician, if the device is “verified” due to patient data and/orpayment information meeting all relevant criteria (i.e., a patient hasmet all defined compliance criteria and the patient is paid up throughthe current month, etc) then the device may simply be verified andinformation is sent which allows the neurostimulator 51 a to operate foran upcoming period such as another month, after which the user must“renew” the neurostimulator 51 a.

In step 242, the patient or administrator operates the neurostimulator51 a to provide a treatment session. In step 244, the neurostimulator 51a determines whether the device is “verified” which may simply entaildetermining if a treatment credit is available. However, even if atreatment credit is available, if the patient has not met compliancecriteria or if a prescription for the patient using the device hasexpired then the device 51 a may not provide stimulation. If the deviceis verified then the neurostimulator may provide treatment and performcontingent operations such as managing a parameter value associated withtreatment credits. If it is determined in step 244 that there are nomore available treatment credits or that the device is not “verified”,then the user must return to step 240 to purchase additional treatmentcredits before another treatment session may be performed or the devicemay be otherwise verified.

If a treatment credit is available, and the device is verified then thenerve stimulation 51 a performs a treatment session using one of thetreatment credits purchased and transferred to the neurostimulator 240.In performing the treatment session, the neurostimulator 51 a activatesthe pulse generator so that current pulses of a stimulation signaltraverse the stimulation site during the treatment session by passingbetween stimulators such as from the TENS electrode 88 to thepercutaneous electrode needle 28. If the device is operated on apay-per-session basis then after a treatment session is performed, thenumber of available treatment credits is reduced by one. Step 242 isthen repeated when another treatment session is desired. In embodiments,the system allows for devices to be verified although a treatment creditvalue may be negative reflecting a treatment credit deficit.

Methods for providing therapy are shown in FIG. 13A, where in a firststep 250, a needle electrode is percutaneously inserted in the leg at orbelow the knee at a position known, or determined to be, appropriate forstimulation of the SAFN.

In a second step 252, an assessment procedure is performed wherein thesignal provided by a neurostimulator 51 b is increased in steps (e.g.,0.5 uA) from a starting value to a value at which the patientexperiences tingling, warmth, pressure, vibration or other similarsensory event which has been determined to indicate that the SAFN isstimulated. Typically this should include a sensation that radiates awayfrom the site of the electrodes and often will spread down the leg andeven towards the hallux (or up the leg if a stimulator is located nearthe foot). The stimulation level is then increased from above nerverecruitment threshold to a level that is greater but not painful to thesubject and is provided during treatment. If the patient is not able tofeel “tingling”, or if it occurs at an amplitude that is higher thanwhat is expected for that patient (compared to previous sessions of thatpatient) then the needle electrode may be re-oriented or inserted in anew location, and the assessment is done again. The stimulation is thentypically halted while the assessment is done for the PTN stimulationsite. An assessment mode of the device may provide an assessment signalwhich increases its amplitude or pulse width in order to allow thepatient to better confirm the spreading sensation.

In some embodiments for combined SAFN and PTN stimulation, a step 254may be done in which a needle electrode is percutaneously inserted inthe foot or leg at a position known, or determined to be, appropriatefor stimulation of the PTN.

In step 256, the signal provided by the second neurostimulator 51 a (ora second stimulus generator of neurostimulator 51 b) is increased insteps of 0.5 uA from a starting value to a value at which the patientexperiences a foot twitch which indicates that the PTN is stimulated.That level is the used to adjust the stimulation amplitude that isprovided during treatment. If no foot twitch is seen or measured from asensor, or if the subjective sensation of a muscle response occurs at anamplitude that is higher than what is expected for that patient then theneedle electrode is removed, inserted in a new location, and theassessment is done again. The stimulation is then typically halted forthe PTN stimulator.

In the fifth step 258, combination stimulation is provided to both theSAFN and the PTN according to a selected therapy protocol whereby thesignals for the first and second stimulators are provided and therapycontinues for the selected therapy interval such as 30 minutes. Forexample, the stimulation may alternate between the SAFN and the PTN, mayoccur simultaneously, or may occur as otherwise designed. A variant ofthis method can include using two stimulation sites which are both SAFN.Sites can be selected on the same or different leg. Although this methodis oriented for percutaneous stimulation, a similar method can be usedfor combination TENS therapy where the stimulation of the SAFN and PTNare assessed separately before stimulation therapy is provided.

As shown in FIG. 13B, in a first step 260, at least a first TENSelectrode is attached to a subject's leg at a position known, ordetermined to be, appropriate for stimulation of the SAFN, while atleast a second TENS electrode is placed nearby, preferably lower on themedial surface of the leg or at a location such as the inner sole of thefoot.

The TENS approach to electrically stimulating the SAFN for the treatmentof OAB will typically involve placing at least one pair of surfaceelectrodes placed on the medial aspect of the lower leg (e.g. step 260of FIG. 13B), with one electrode slightly below the knee. Placement ofthe electrodes may target the SAFN branches that travel subcutaneouslyfrom the level of the knee down to the ankle but electrodes on themedial aspect of the sole of the foot may also be found to provideeffective bladder modulation. Anatomical studies in human cadaversreport a high degree of variability in the anatomical location of theSAFN branches (Wilmot, V. V. and Evans, D. J. R. (2013), Categorizingthe distribution of the saphenous nerve in relation to the greatsaphenous vein. Clin. Anat., 26: 531-536). As such, the optimalelectrode configuration may vary from one patient to another. Ingeneral, the SAFN emerges as either single or multiple fascicles at thelevel of the knee, immediately posterior to the medial condyle of thetibia. These travel along the medial aspect of the leg and can belocated either anterior or posterior to the saphenous vein.Anatomically, the saphenous vein is located along the posterior marginof the tibial bone. Therefore, the main SAFN may be located moreanterior or posterior to the posterior margin of the tibia. Placing theelectrode too posterior to the tibia may result in the electrode beingdirectly over the medical gastrocnemius muscle, which may beelectrically activated during stimulation. This unintended muscleactivation may cause discomfort to the patient. If this occurs, theelectrode should likely be repositioned and stimulation tried again toavoid this.

In a second step 262, an assessment procedure is performed wherein thesignal provided by a neurostimulator 51 b is increased in steps (e.g.0.5 uA) from a starting value to a value at which the patientexperiences a tingling sensation radiating along the leg which indicatesthat the SAFN is being modulated. That level can then be used to adjustthe stimulation amplitude that is provided during treatment 266. If thepatient is not able to feel the expected sensation, or if it occurs atan amplitude that is higher than what is expected for that patient(compared to previous sessions of that patient) then at least the firstTENS electrode is removed, applied to a new location on the medialaspect of the leg, and the assessment is done again. Rather than movinga single electrode, an electrode array or neurostimulator having pairsof electrodes can be moved.

During assessment of the SAFN 262, a doctor or patient may be instructedthat correct electrode placement and electrical stimulation of the SAFNmay be determined if a patient can confirm a “tingling” sensation thatradiates below the site of stimulation. If stimulation evokes a footmotor response, then the selected electrode placement and/or selectedstimulation signal may be (co-)activating the tibial nerve. In thiscase, it may be beneficial to change the location of one or moreelectrodes and re-assess.

With respect to adjusting stimulation characteristics 266, amplitude istypically set at the maximum value that is tolerated by the patient inthe case of PTNS treatment. This may also occur in SAFN therapy, or theSAFN stimulation protocol may be distinct. For example, the protocol mayinstruct a user to determine the maximum stimulation and then reduce theamplitude by 10%, 20% or 50%, as long as nerve activation still occurs.In order to ensure that TENS is effective, it is likely that the minimumamplitude used for treatment will be defined by the amplitude at whichthe proximal electrode (e.g., location 29 b) evokes a sensory perceptthat spreads away from the electrode down the leg. This indicates thatthe subcutaneously located SAFN fascicle(s) are activated by theproximal TENS electrode.

In an embodiment, at least one surface electrode will be placed withinthe upper one-third of the lower leg to target the main fascicle(s) ofthe SAFN. The return electrode may be placed at more distal locations,such as the mid-point between the knee and the foot (29 d or anterior tothis location), 5 cm cephalad to the medial malleolus (29 c), or themedial aspect of the sole of the foot (location 88). When stimulationcharacteristics of the signal are adjusted 266, polarity can be assignedas part of the stimulation protocol. The polarity of each electrode maybe set to positive (anode) or negative (cathode), or this may beadjusted depending on the preference indicated by the patient based uponsubjective comfort, or this may change during the stimulation.

In the fifth step 268, stimulation is provided to at least the SAFN ofone leg according to a selected stimulation protocol for the selectedtherapy interval such as 30 minutes. The method can also perform theassessment or treatment bilaterally or choosing the leg that showsstronger recruitment.

FIG. 14 shows a system 8 a for providing TENS stimulation including anelectrode array 270 having three TENS electrodes 30 j,k,l which areconnected by conduits 85 a,b,c to three connector sockets 272 a whichreside within a receptor base 274. Rather than connector sockets aconnector can contain routing circuitry and other electronics which canbe under control of the neurostimulator 50 a or the programmer 70. Afirst strap 276 can be configured as first 276 a strap portion andsecond 276 b strap portion which are connected to the array 270 on theirproximal ends and which have fastening portions on their distal ends(e.g. Velcro) or which may be made of a sports wrap type material thatallows the strap portions to grip each other without sticking to the legof the user 6. A second strap 278 may also be provided on the bottom endof the array 270. Rather than being connected permanently to the array270 the straps can be configured to snap onto the array. The receptorbase can be formed of plastic or rubber and is shaped to receive aneurostimulator 50 a which snaps into the connector sockets 272 a toreversibly attach the neurostimulator 50 a to the electrode array 270.The array can be formed of a foam, silicone, or rubber material which isflexible and which provides for routing of the conduits 85 to the TENSelectrode pads 30. The view shown is the top side of the array 270 andthe bottom side is disposed with 3 areas of electrode hydrogel orconductive material provided on the TENS electrodes for connecting tothe user's skin. There is also provided a user/physician programmerwhich may be realized as a smartphone on which a software applicationhas been downloaded or by a customized user interface device (a batterypowered remote control) which communicates with the neurostimulator 50 aor electronics provided on the array 270 in a wired or wireless manner.When provided as a kit, the array 270, neurostimulator 50 a, programmer70, and instructions for use 276 may be included. In an embodiment, thearray 270 is designed to be disposable and provide for approximately 1month of use.

In an embodiment, the stimulation protocol can stimulate by referencingthe first TENS electrode 30J to the second and third electrodes 30 k,lif the patient can tolerate this. Alternatively, combinations ofstimulation circuits which include electrodes 1 and 2, 2 and 3, 1 and 3,or 1 referenced to 2 and 3(or 2 referenced to 1 and 3) can be selectedbased upon patient comfort or the success of different electrodecombinations to recruit the SAFN and produce a tingling sensation thatradiates down a subjects leg from the upper-calf where the array ispositioned during use. Allowing a user to selectively and programmablyactivate unique pairs from the 3 electrodes based upon user input canallow a patient to select a stimulation montage that stimulates the SAFNwell without having to physically remove and replace the array to obtainsuccessful positioning of electrodes. It also may be that in somesubjects increasing the size of the electrode field serves to recruitthe nerve better, while for others only 2 electrodes work better. In anembodiment, only two TENS electrodes (or more than 3) are provided onthe array. Electrode combinations can be determined during assessment262.

FIG. 15 shows top (front) and bottom (rear) views of a neurostimulator50 a on the top and bottom of the figure, respectively. The top side ofthe neurostimulator shows a display 79, a power button 14, a menucontrol 18, and dedicated buttons 16 which may be used for example, toincrease or decrease stimulation amplitude. Interface port 114 allowsfor powering the device or for wired communication with other systemcomponents. The bottom view shows three connector sockets 272 b whichconnect to the corresponding sockets 272 a on the neurostimulator.Although the neurostimulator 51 b shown in FIG. 2 only has one connectoron its bottom surface for connecting to a TENS electrode, the other 2connectors can simply be inactive during percutaneous stimulation whenthat stimulator is designed to be used for providing therapy bothpercutaneously and transcutaneously.

In this system patients can begin OAB treatment by receivingpercutaneous stimulation in a clinic for a number of sessions and thenthe neurostimulator can be used by the patient to provide TENS byinterfacing with an electrode array. While the treatment credits can beused to manage in-clinic percutaneous stimulation, these can also allowfor a month of TENS treatment per credit, when the neurostimulator isused at home by a single patient rather than in the clinic for manypatients.

Kits and Methods for Providing TENS of the SAFN For OAB Treatment.

In an embodiment, the invention is realized as a kit having at least twoTENS electrodes 88 configured to receive a stimulation signal from aTENS neurostimulator 50 a. The stimulation signal can be providedaccording to a stimulation protocol that is defined for stimulation ofthe SAFN for the treatment of overactive bladder. The kit also includesinstructions 276 for using the neurostimulator for the treatment ofoveractive bladder disorder which includes instructing a user toapplying at least one of the 2 stimulators on the medial aspect of theleg below the knee for the treatment of the SAPH nerve. In instructions276 may alternatively include instructions to place at least one of thetwo TENS electrodes on the inner side of the leg in the area near theupper calf and then provide a stimulation signal in order to determineif at least one of a tingling, vibrating, buzzing, pressure,electrotactile tactile sensation, warmth, or tickling sensation isexperienced as radiating away from the location of at least one of thetwo electrodes. Further, the instructions direct a user in the casewhere the sensation is not experienced, and the application of thestimulation signal fails to produce a radiating sensation indicatingthat the saphenous nerve has been stimulated, then performing the stepof either increasing the stimulation signal or adjust the position of atleast one of the two TENS electrodes. In the case where the sensation isexperienced then provide a stimulation session using a stimulationstrength that does not cause pain.

In one embodiment, determining if a sensation occurs includesdetermining if the sensation is radiating away from an electrode anddown the leg towards or into the foot. Alternatively, instructions mayalso include directions to place a second lower electrode near themedial malleolus or the sole of the foot and determining if a sensationoccurs includes determining if the sensation is either radiating awayfrom the first electrode and down the leg, or away from the second lowerelectrode an up the leg.

The instruction 276 can include or be provided in paper or as part ofthe user interface module which has multimedia ability for providinginstructions via the neurostimulator 10 a or the programmer 70.

In an embodiment, the at least two TENS electrodes can be realized aspart of an accessory such as a garment or an electrode array thatpositions the electrodes on the medial aspect of a patient's leg with atleast one electrode positioned 1-4 inches below the knee.

An external patient programmer can be configured to communicate with andprovide user control of the neurostimulator and at least one of theneurostimulator and external patient programmer are configured tomonitor usage and assess compliance with respect to a treatment programthat is related to treatment of overactive bladder and to providepatient alert reminders related to a stimulation program that is definedfor the treatment of overactive bladder.

In an embodiment, the stimulation signal is defined to be a pulse trainmodulated at 10 Hz, 20 Hz, or can be a signal that roves between 10 and20 Hz. The stimulation signal may be defined to be at least one of:slightly above (e.g. 0.5 or 1 mA) skin threshold (Tskin) which is thelevel at which the stimulation is first felt and slightly below maximumtolerance (Tmax) which corresponds to the level at which a userexperiences discomfort or pain. A signal may also be defined to rovebetween Tskin and Tmax, by continuously or periodically adjustingamplitude, stimulus pulse width, and/or period as may be defined for asinusoidal waveform.

In an embodiment, a system component such as the neurostimulator orprogrammer determines the therapeutic protocol for a given week orlonger periods using a pre-defined schedule stored in its memory. Theschedule may be modified according to various factors such as time sincethe first therapy session, number of stimulation sessions provided sincethe start of therapy, rate of stimulation sessions provided since thestart of therapy. Additional adjustment may be made based uponassessment of patient input data which indicates improvements,worsening, or no change in symptoms as calculated upon patient inputdata.

In embodiments, at least one system component operates at least oneaccelerometer and is configured to analyze the accelerometer data inorder to determine if a user is active or ambulatory using at least oneof activity data and orientation data. The accelerometer data maybeanalyzed to determine if the patient is, for example, walking, gettingout of bed, moving with a gait that is over a selected rate. In thiscase, a modification the system may modify operation such as pausing ordecreasing the provision of stimulation until the accelerometerdetermines that the user has stopped being active.

In embodiments, the instructions may also incorporate methods andguidelines reviewed in other parts of this specification. Additionally,because percutaneous saphenous nerve stimulation at the level of theknee can be used to treat individuals with pain, the kit may beindicated for providing relief both pain and OAB. In this instance theinstructions that are provided within the kit may instruct a user selectthe treatment mode related to the desired therapy and may also beinstructed to position electrodes or an electrode array differentially.

In an embodiment, a method of treating an overactive bladder of a personsuffering symptoms of the disorder includes the steps of applying TENSelectrodes for stimulation 260 which can include establishing at leasttwo transcutaneous electrical neural stimulation (TENS) electrodes 30and establishing a neurostimulator 10 a configurable to provide atreatment stimulation signal to the TENS electrodes according to astimulation protocol that is defined in, or selectable using, astimulation module 54 for stimulation of the SAFN for the treatment ofthe patient's OAB symptoms. This also includes positioning at least oneof the two TENS electrodes on the inner side of the patient's leg 6 inthe area near the upper calf. An assessment procedure 262 can includethe steps of actuating said neurostimulator 10 a to provide a teststimulation signal and assessment in order to determine if at least oneof a tingling, vibrating, buzzing, pressure, electrotactile tactilesensation, warmth, or tickling sensation is experienced which radiatesaway from the location of at least one of the two electrodes. In theassessment 262 two steps may occur which include (1) when application ofthe test stimulation signal fails to produce a radiating sensationindicating that the saphenous nerve has been stimulated, then performingthe step of either increasing the test stimulation signal or adjustingthe position of at least one of the two TENS electrodes and (2) when thetest stimulation signal produces the radiating sensation, then providingstimulation treatment 268 using a stimulation signal strength which isnot painful to the patient. The strength can be iteratively assessed oradjusted during therapy in the case that the patient threshold for painchanges.

In the method, the step of determining if a sensation occurs may includethe step of determining if the sensation is radiating away from anelectrode and down the leg towards or into the foot. Alternatively, theapplication step may include the steps of providing instructions toplace, or placing, a second lower electrode so that it is verticallydisplayed from the first electrode and near the medial malleolus or thesole of the foot and determining if a sensation occurs which can beeither radiating away from the first electrode and down the leg, or awayfrom the second lower electrode and up the leg.

The method may also include the step of providing user instructions, orinstructing a user directly, and these can be related to actuating saidneurostimulator to provide a test stimulation signal and performassessment 262 and providing stimulation with various protocols 268. Theuser instructions can include at least one of: written instructions;illustrations of the leg with graphic depictions of the location on themedial surface of the leg where the TENS electrodes should be placed;illustrations of the leg with graphic depictions of the location on themedial surface of the leg where a TENS array should be placed;instructions provided by a mobile device app or a mobile device; anaudio-message of instructions; verbal instructions; instructions to usea device such as an ultrasound, infrared, or electrical impedance devicein order to located the saphenous nerve or saphenous vein; instructionsprovided in combination with either a virtual reality or holographicdisplay; instructions provided by a mixed media technology such as aDVD, and, a website address where user instructions are provided.

In the method, at least two TENS electrodes can be realized as part ofan accessory such as an electrode array 270 that positions theelectrodes on the medial aspect of a patient's leg, or a garment 220.Additionally when the at least two TENS electrodes are realized withinan electrode array 270 that is designed to be connected to at least oneband 276 that is configured to be wrapped around the calf of a patientand to position the array vertically along the inner side of the leg andthe first electrode is above the second electrode. The band may beconfigured to wrap around the area of a patient's upper calf to secureand bias the electrode to the calf The band or garment 220 can beconfigured to be attached to at least one electrode and to wrap aroundthe area of a patient's upper calf, mid-calf, or entire leg to secureand bias the one electrode to the area between the upper calf muscle andthe tibia.

The method may further include providing or operating an externalpatient programmer 70 which is configured to communicate with andprovide user control of the neurostimulator and at least one of theneurostimulator and external patient programmer are configured tomonitor usage and assess compliance with respect to a treatment programthat is related to treatment of overactive bladder and to providepatient alert reminders related to a stimulation program that is definedfor the treatment of overactive bladder. Additionally, at least one ofthe neurostimulator and external patient programmer are configured witha user interface module 76 configured to query about bladder activity,bladder pressure, urinary leakage and/or urgency episodes measured bywearable or implantable sensors. In an embodiment, at least one of theneurostimulator and external patient programmer are configured to querythe patient about a symptom characteristic such as severity or frequencyrelated to overactive bladder symptoms and to store the response.Further, at least one of the neurostimulator and external patientprogrammer are configured to allow the patient to input informationrelated to a bladder diary, including if a void event was associatedwith urgency or leakage. These may also be configured to query thepatient to input information about whether any voiding events occurredduring night, whether voiding events awoke the patient, or whethervoiding events were accompanied by urgency or leakage.

The method can further include setting, instructing, or providinginstructions related to setting a stimulation protocol that is definedfor stimulation of the SAFN for the treatment of the patient's OAB whichincludes setting the stimulation signal to be at least one of: a signalbetween 5 and 20 Hz, a 10 Hz signal, a 20 Hz signal, and a signal thatroves between 10 and 20 Hz. The stimulation signal can be defined in thestimulation module 54 to be at least one of: skin threshold (Tskin),maximum tolerance (Tmax), and a signal that roves between Tskin andTmax, by continuously or periodically adjusting amplitude, stimuluspulse width, and/or period in the case of a sinusoidal waveform.

The method can also include an external patient programmer 70 that isfurther configured to graphically display data related tooveractive-bladder-related symptoms as summary statistics or trendcharts. The external device or programmer 70 can also determine thetherapeutic protocol for a given week or longer periods using rules orlookup tables of the compliance module 200 based upon factors such astime since the start of therapy, number of stimulation sessions providedsince the start of therapy, rate of stimulation sessions provided sincethe start of therapy, and improvements, worsening, or no change insymptoms as calculated upon patient input data.

The method can also include providing and operating an accelerometer forat least one system component and the system 10 a is configured toanalyze the accelerometer data in order to determine if a user is activeor ambulatory using at least one of activity data and orientation data.The accelerometer data maybe analyzed to determine if the patient is,for example, walking, getting out of bed, moving with a gait that isover a selected rate. In this case, the system may modify operation suchas pausing or decreasing stimulation until the accelerometer determinesthat the user has stopped being active.

In an embodiment a system for transcutaneous electrical nervestimulation in humans includes a housing 12 a stimulation module 54having stimulation generator mounted within the housing for electricallystimulating nerves and an electrode array 270 releasably mounted to thehousing and connectable to the stimulation generator, the electrodearray comprising a plurality of at least two electrodes 30 forelectrical stimulation of nerves. The user interface module 76 canprovide at least one user control 16 mounted to the housing andelectrically connected to a user interface module 76 working with thecontrol module 52 to control the stimulation generator for controllingat least one characteristic of a stimulation signal generated by thestimulus generator. The sensing module 55 can provide monitoringcircuitry mounted to the housing 12 and electrically connected to thestimulation means for monitoring impedance in order to assess electrodecontact with patient skin 6. A user interface module 76 mounted withinthe housing 12 and electrically connected to the control module 52 forcontrolling the stimulus generator. A user display can be part of theinterface module 76 and mounted to the housing and electricallyconnected to the control user interface module 76 and the monitoringcircuitry of the sensing module 55 for displaying the status informationrelated to the device 50 a. At least one strap 276 can be attached to atleast one of the housing and the electrode array 270 and the the strapis configured to hold at least one of the housing 12 and the electrodearray 270 so that the array stimulates a specific anatomical location totreat OAB by stimulation of the SAFN using at least two verticallydisplayed electrodes 30. Preferably, the location is the medial surfaceof the upper calf area between the calf muscle and the tibia.

Co-Activation and Related Investigations of PTN and SAFN Stimulation.

The current invention is based upon the recent finding by the inventors,using both pre-clinical and clinical data, that the SAFN can be used asa target in the treatment of OAB and related disorders. Results of arecent study are shown in FIGS. 14 to 19. Co-activation of SAFN due topercutaneous stimulation of PTN was explored. This study was conducted,in part, due to the apparent differences in the stimulation amplitudesused to provide PTNS therapy in patients and those used in pre-clinicalanimal studies. In patients, PTNS is applied near the foot motorthreshold (defined as “1T”). Studies in anesthetized cats and rats showthat larger stimulation amplitudes (>2T) are needed to inhibit bladderfunction. Not only are these amplitudes markedly higher than those usedclinically in humans, but these findings also suggest that bladderinhibition is achieved, at least in part, by electrical recruitment ofsmaller diameter (Aδ) myelinated fibers as well as co-activation.Preliminary work in the inventors laboratory (PY) at the University ofToronto using a rat model has also shown that stimulation of the SAFNwhich innervates the entire medial side of the lower leg—can evokebladder-inhibitory reflexes, and further that it can do so usingamplitudes that are as low as 25% of those used for PTN.

The anatomical proximity of the PTNS electrode (an uninsulated needle)to SAFN branch(es) that innervate and also pass through the regionposterior to the medial malleolus also motivated this study. Studies inhuman cadavers show that a major posterior SAFN branch is found inapproximately 87% of sampled subjects. This led us hypothesize thatbenefits of PTNS therapy may often involve concomitant activation of aportion of SAFN fibers. Given the challenges of testing this hypothesisin patients, we conducted a computational study that simulated PTNS in amodel of the human lower leg. The effects on the relative electricalrecruitment of the TN and SAFN for needle electrode location, needleelectrode type (uninsulated vs. insulated) and stimulation amplitudewere explored.

FIG. 16, shows a cross section of the human ankle used to model the PTNand SAFN (a hypothetical distribution of 5 branches labeled S-A to S-E)that was extruded to a depth of 20 cm. (left side) and also shows thatthe relative activation of the TN and SAFN branches achieved by PTNS wasstrongly dependent on the depth and anterior-posterior position of theuninsulated (top row) and insulated (bottom row) needle. The modelpredicts that—when compared to the PTN—the uninsulated needle willactivate SAFN (branches A-to-C and branches D-E) at lower amplitudeswhen the electrode is located more posterior or superficial to the PTN,respectively. In contrast (bottom row), the insulated needle is markedlymore selective in electrically activating the PTN (i.e., lower thresholdthan SAFN) across the 5×10 grid. The top row clearly shows that with anun-insulated needle, the spread of co-activation is prevalent. Twodifferent methods were used to predict excitation of the PTN and SAFN:the activating function (AF) and the McIntyre-Richardson-Grill (MRG)axon model. Within a 5×10 array of needle electrode positions (spacingbetween grid locations=0.2 cm), electrical stimulation was simulated ateach location using various stimulation amplitudes relative to PTNthreshold (0.5T to 4T). At each location the relative excitability ofPTN and SAFN was quantified by a selectivity ratio (SR) (ratio of the AFof the PTN to the AF of the SAFN), reflecting the relative activation ofthe two target types. At each level of PTN stimulation (0.5T to 4T), the% of electrically-activated SAFN branches was also determined using theMRG model.

FIG. 17 plots the percentage change in SR and indicates the averagedecrease in threshold for activating a SAFN branch can be between about100% (branches A, B, and E) and 10,000% (branches C and D), when theinsulated electrode is replaced with an uninsulated electrode.

FIG. 18, plots the percentage of SAFN branches that are activated whenelectrical stimulation is applied at each location within the 5×10 grid(top row: uninsulated needle, bottom row: insulated needle). Whenapplying PTNS with an uninsulated needle (as occurs clinically inpatients), the computational model shows that significant co-activationof SAFN is achieved, not only at amplitudes equal to or greater than thefoot motor threshold (≧1T) but also at amplitudes below IT. Depending onthe location of the electrode tip, anywhere between 20% and 100% of SAFNbranches are activated by the PTNS electrode. In contrast, electricalstimulation delivered with an insulated needle appears more effective atavoiding SAFN branch activation. However, as shown in FIG. 19, selectivePTN activation is possible only when the electrode tip is placed withinapproximately 0.2 cm (1T) to 0.02 cm (4T) from the TN.

FIGS. 16 to 19 results suggest that in humans it is extremely likelythat percutaneous stimulation of the PTN with an uninsulated needleprovides unintended activation of SAFN fibers. Co-activation of SAFNfibers during PTNS can potentially influence the therapeutic outcome inpatients by providing at least supplementary, if not primary, bladderinhibitory effects. Further, results from this computational studysuggested that targeting the SAFN directly may provide improvedtherapeutic response. We have now shown in humans using percutaneousstimulation of the SAFN near the knee which is unlikely to co-activateany tibial nerve fibers.

These data may support an embodiment of a method for modulating voidingactivity of a patient that comprises the steps of implanting at leastone electrode and applying a stimulation signal from the implantedelectrode while the electrode is closer to the SAFN than the PTN toprovide improved benefit. If the electrode is multipolar and isconfigured to use field steering then the method may include usingmultiple contacts to steer the field towards a SAFN target.Alternatively, both the SAFN and PTN can be stimulated more reliably byspatially directed fields and/or well positioned electrodes specificallyoriented towards each target. Accordingly, if a coin-shapedneurostimulator is implanted near the PTN, electrode contacts can beprovided on its top and bottom surfaces to achieve selectiveneurostimulation.

A preclinical study was conducted in twenty-three Sprague-Dawley rats,where animals were initially anesthetized under isoflurane (3-5%) andlater transitioned to urethane following surgical procedures (1.2 g/kg,IP). The bladder dome was catheterized and connected in series to apressure transducer and infusion pump. An incision along the medialaspect of the lower leg provided access to the SAFN, caudal to the kneejoint where a bipolar stimulating nerve cuff electrode was placed. Apair of de-insulated stainless steel wire electrodes was inserted intothe external urethral sphincter (EUS) muscle using a perineal approach.The bladder was emptied and then continuously filled with saline(infusion rate=0.08−0.1 ml/min) throughout the experiment. Reflexbladder contractions were confirmed by rapid increases in pressure withconcomitant bursting EUS activity.

Bladder function was quantified by the bladder contraction rate (BCR). Atotal of 121 stimulation trials were conducted where the pulse width wasset at 200 us while the stimulation parameters were varied as follows:Frequency: 2 Hz-50 Hz; Amplitude: 25 uA-100 uA; Duration: 10 min-40 min.The baseline BCR averaged to 0.6±0.12 contractions/min.

As shown in FIG. 20, low amplitude stimulation trials (10-minutes each)at 20 Hz was most effective at achieving significant reductions in theaverage BCR (50.2±5.0%, range: 33.8%-78.1%), during both theintra-stimulation and post-stimulation (38.7±6.2%) periods. As shown inFIG. 21, the effectiveness of SAFN stimulation was also confirmed by thevery high percentage of rats that exhibited an inhibitory response at 20Hz (100%).

The decrease in bladder activity seen in rat data should reduce bothfrequency of voids and urgency related to voids in humans. In order todetermine if therapy is providing benefit the system can be configuredto ask users about their symptoms. Accordingly, FIG. 22 shows a screenasking a user to provide input about bathroom frequency while FIG. 23shows a screen asking a user to provide input about urgency. Theresponses to these questions can be stored and can guide therapy as willbe disclosed.

FIG. 24 shows that by increasing the duration of the stimulation trial(amplitude set at 25 μA), we observed a growth in instances wherebladder function was markedly inhibited (i.e., atonic bladder). Thisloss in bladder function occurred in 20% of experiments following 20minutes of 10 Hz SAFN stimulation, and in 50% of experiments following40 minutes of 10 Hz SAFN stimulation. It was less frequently observedfollowing 20 Hz SAFN stimulation. This stimulation-evoked loss inbladder function is shown in FIG. 25, where long duration (40 minute)continuous stimulation of SAFN at 10 Hz is coupled to low stimulationamplitudes. After an initial decrease in BCR (i.e., longer intervalsbetween contractions) during the intra-stimulation period, we observe agradual transition towards a loss in bladder function near the end ofthe stimulation trial period. This was characterized by a gradualincrease in the basal (i.e., resting) bladder pressure, a significantdecrease in the bladder contraction amplitude (49.0±10.5%), and also anincrease in the threshold bladder pressure at which voiding occurs(17.6±4.8%). This transition period is followed by random fluctuationsin bladder pressure along with passive leaks (single drops) through theurethral meatus. The duration of this loss in bladder function wasapproximately 30 to 50 minutes.

When considering these pre-clinical data, effective clinical treatmentof OAB symptoms with at least SAFN stimulation may be achieved at (1)the highest amplitude tolerated by patients, (2) frequency set at 10 Hzor 20 Hz, and (3) electrical stimulation applied for longer periods(e.g., 5 or 10 hours per day) in more severe patients. Alternatively, itmay be found in patients that electrical stimulation at the sensorythreshold, with as little as 30 minutes every week is sufficient toproduce improvements in OAB symptoms. The post-stimulation responseevoked by SAFN stimulation in this preclinical data may be akin to whatis seen in humans following PTNS. While additional work is needed tocharacterize the reflex pathways for SAFN stimulation, this preclinicalwork provides evidence that supports the potential for using SAFNstimulation to treat patients.

eTENS

In embodiments of the invention the neurostimulator uses an externalstimulator such as a TENS surface electrode and an implanted passivecomponent (IPC) which can be realized as a conductive nerve cuff,conductive rod, a thin conductive plate or mesh that is suitablyconfigured with an anchoring means in order to maintain its position ina patient, or even a conductive gel. FIG. 26 and FIG. 27 show a modeledembodiment of a surface electrode, target nerve surrounded by tissue andlocal anatomy, and an IPC. Systems and methods related to the inventiveprinciples that are now described are termed enhanced transcutaneouselectrical stimulation or “eTENS”. The eTENS principles are still beingevaluated and the data provided here are shown for illustrationspurposes and are not intended to be limiting.

FIG. 28 shows a schematic of a circular TENS electrode 30N which isconfigured to provide monopolar stimulation. A second TENS (return)electrode is located far away on the skin of the patient (not shown indiagram). An IPC 212 that is separated from the TENS electrode at itsproximal end by a distance 211A and its distal end by a distance 211B,which are approximately equal. The IPC is also separated from the targetnerve at its proximal end (212A) by a distance 211C and its distal end(212B) by a distance 211D. The figure is not to scale and the distance211C an 211D are typically made to be as small as possible so that theIPC is either in contact with the target nerve, or almost in contact. Inthis example the IPC is implanted to be aligned with the target nerve.If the target nerve is not parallel to the skin surface and TENSelectrode then 211A may be larger or smaller than 211B, but the distance211C and 211D should remain approximately equal so that the IPC isaligned with the nerve approximately along its total length or for themajority of its length. Accordingly, the IPC is not designed to serve asa conduit which physically routes electrical charge from a pulsegenerator (or a relay device such as a receiver terminal) to a targetnerve. Instead, evidence is shown here supporting that the enhancementof neural activation is achieved by a different mechanism that modifiesthe electrical current passing through and around the IPC, as well asthe target nerve.

Although the figure shows a monopolar montage, in order to realize theeTENS system, the interface ports 83 of the neurostimulator 50 cancommunicate with bipolar electrode components including two contactsseparated by space or a non-conductive surface that has been paired withthe IPC length and positioned relative to the IPC to provide improvedeTENS. The two contacts may serve as an anode and cathode respectivelyor may both be anode or cathode with another electrode, locatedelsewhere, serving to complete the circuit. The anode and cathode statuscan change as a function of the stimulation waveform.

FIGS. 29a-c show the effects of eTENS (measured by relative excitation)are dependent on the relative location of the IPC (e.g., nerve cuff) andthe surface electrode. In this example, the IPC achieves more‘enhancement’ when the nerve cuff is located at the edge of the TENSelectrode that corresponds to where the return electrode is located. Thereturn electrode is located at a position greater than 16 cm along thenerve (refer to x-axis). The TENS electrode is represented as the darkbar near the x-axis, while each data point corresponds to the mid-pointof the IPC. The black bar in each plot reflects the length of the TENSelectrode, and the IPC is 1 cm. Monopolar stimulation is modeled.

FIG. 30 shows that ‘enhancement’ of neural activation is achieved whenthe electrical conductivity of the IPC is at least 3 orders of magnitudegreater than that of saline (˜1 S/m). FIG. 31 shows that the effects ofeTENS can be further increased by increasing the length of the IPC.

As part of the mechanism of eTENS, which is different from routing thestimulus current, FIG. 32 shows that the electric potential along thenerve cuff and within the endoneurim. The nerve cuff creates anisopotential surface within the body; while the endonerium shows anelectric potential gradient that varies spatially along the nerve. Theinset is shown, in an expanded view, at the top of the figure.

FIGS. 33A to 33D show radial and axial current characteristics along aperipheral nerve with a length of 20 cm. The TENS electrode is centeredat the 10 cm location, and the IPC is centered at 16.5 cm. The goal ofplacing the IPC distal to the TENS electrode was to show the effect ofthe IPC on the externally applied stimulus current. Compared toconventional TENS, FIGS. 33A and 33C show that the IPC generates radialcurrents at the site of implant. In FIGS. 33B and 33D, the axial (i.e.,longitudinal) current along the nerve decreases by over 50% within theIPC. The amplitudes used in these simulations are sub-threshold to nerveactivation. The positive radial current at the outer surface of theendoneurim (centered at 10 cm) is indicative of the cathodic currentapplied through the surface electrode. The radial current generated atthe nerve cuff, which is located 7.5 cm distal to the center of thesurface electrode, appears as a virtual anode-cathode pair. In FIG. 33Bthe longitudinal current is largest between the surface electrode andthe distal ground, but the presence of the nerve cuff causes a verylarge decrease in the longitudinal current within this highly-conductivecylindrical shell.

FIG. 34A provides visualization of current density vectors generated bya simulation of eTENS (corresponding data shown in FIG. 33A-D). Aninflux of current is seen within the proximal half of the IPC (closer tothe active TENS electrode) and an efflux of current is observed withinthe distal half of the IPC (closer to the return electrode). The currentdensity vectors point in the opposite direction when looking outside theIPC. Current is pointed away from the proximal half of the IPC; whereasthe current is drawn towards the distal half of the IPC. This is createdin part by the isopotential surface of the nerve cuff. On the right sideof the figure the potential in the nerve cuff is lower than thepotential in the surrounding tissue and so current flows towards thenerve cuff, while on the left side of the figure current flows into thesurrounding tissue. This phenomenon is explained by (1) the electricpotential gradient created between the (anodic) return electrode(electrical ground) and the cathodic TENS electrode (negative potential)and (2) the isopotential field of the IPC. The proximal half of the IPCis at a higher potential than its surroundings (both inside and outsidethe cuff); while the opposite is true for the distal half of the IPC. Asa result, current will flow away from the proximal half of the IPC; andcurrent will flow towards the distal half of the IPC. In effect, the IPCserves as a ‘virtual’ cathode. The corresponding ‘activating function’of a single nerve fiber shows positive values (i.e., depolarization)within the distal half of IPC, which suggests a ‘virtual cathode’ iscreated by the eTENS system (see FIG. 34B). FIGS. 27-34 are based upon astudy that will be reported in Enhanced peripheral nerve stimulationtechnique for treating overactive bladder: A computational model oftibial nerve stimulation in humans, Roointan, Elder, and Yoo, (InPrep.), incorporated by reference herein.

In accordance with the data provided herein the following embodimentsare supported which do not require rectification of wireless energyusing a coil or rectenna or any circuitry which incorporates this novelphenomenon into the inventive design.

In an embodiment, a transcutaneous nerve tissue stimulation systemincludes a stimulation module having at least one electrical stimulusgenerator and at least a first stimulator, such as a TENS electrode,that is electrically connected to the electrical generator. Thestimulator is adapted to be positioned on the surface of the skin of apatient to provide at least one electrical stimulation signal to thepatient. The system further includes at least a first implanted memberthat is an electrically conductive surface or volume, such as aconductive nerve cuff, conductive rod, or strip of conductive material.The implanted member being positionally located adjacent to orcontiguous with a target nerve tissue.

In an embodiment, the implanted member is located at a predetermineddepth below the skin surface of a patient for enhancing the activationof said target nerve tissue by a signal provided by the stimulator, andthe signal provided by the stimulator is a function of at least the sizeof the stimulator and the predetermined depth of said target tissue.

In an embodiment, the first implanted member has a portion thereof beingelectrically conductive and is devoid of circuitry such as coils,antennae, integrated circuits, diodes, and the like with respect toconverting power provided by the TENS electrode.

In an embodiment, the electrical stimulus generator drives a magnetictransducer having a one or more coils for inducing a field near a targetnerve and in the area of the implanted conductive member, and theimplanted member serves to enhance the activation of the target tissue,relative to what would occur in the absence of the implanted member.

In an embodiment, the at least first stimulator 30N and the at leastfirst implanted member 212 are displaced each from the other by tissuewhich is devoid of an intervening implanted conductive member extendingtherebetween. Further, the implanted member 212 is also devoid of anynon-conductive insulating material that is designed to allow electricalcurrent to be routed from a pick-up electrode relatively close to thesurface of the skin to a stimulating electrode located relatively distalto the skin and relatively proximal to a tissue target, for routing astimulation signal therebetween.

In an embodiment, the implanted member 212 is positionally located withthe majority of its length disposed adjacent to, and approximatelyparallel with, a portion of the target nerve tissue such that it islocated at approximately a depth below the skin surface of a patient andenhances the activation of the target nerve by a signal provided by thestimulator. The stimulation signal is conducted solely throughintervening tissue (e.g., dermis) of the patient.

In an embodiment, the distal 212 a and proximal 212 b tips of theimplantable conductive member, that is devoid of circuitry forconverting the field of the stimulus signal into a stimulation signal,are both located approximately adjacent to the target nerve. Theproximal end 212 b will not be substantially closer to the surfacestimulator than the distal tip 212 b, or vice versa, unless the targetnerves travels from a deep site, to a relatively superficial site in thepatient. Both the distal and proximal sides of the implanted componentwill typically be approximately the same distance from the surface ofthe skin of the patient. The implanted member is positionally locatedadjacent to or contiguous with a target nerve tissue such that it isadjacent to the nerve for approximately the span of its entire lengthfor enhancing the activation of target nerve tissue by a signal providedby the stimulator. The enhancement will be a function of, for example,the distance between the target nerve and the surface of the patient'sskin, the size of the implanted component (e.g., length), and the sizeof the surface electrode.

In embodiments related to eTENS (or TENS), high frequency current bursts(e.g., greater than 10 kHz or 1 MHz) can be provided using TENSelectrodes at the surface of the skin across the tissue where the one ormore implants are located. Although the implantable components often actto stimulate target tissue with stimulation signals that approximatethose delivered by a stimulator at the skin surface, depending uponfactors such as the distance from the surface and the conductivity ofthe implants these may act as low pass filters of these high frequencycurrent bursts, and can generate focused low frequency currents capableof stimulating excitable nerve, muscle, or other tissue. When one ormore implantable components are used to modulate biological activitysuch as altering the function of an internal organ (e.g. vagus nerve formodulating an inflammatory response, cardiac activity, or appetite of anorganism) these may be used as so-called “electroceuticals”.

In an embodiment, a system component such as the physician programmer 70provides simulation modeling using a simulation module 57 related totherapy and model result data. These result data may be used by aphysician, or can be operated upon by control circuitry of aneurostimulation system, to adjust and control the stimulation circuitryin order to provide stimulation to the patient according to astimulation protocol which is adjusted to provide eTENS. In anembodiment, the computer module performing the simulation is adjustedbased upon imaging data scanned from a patient, such as collected MRI orsonography in order to reflect the physical characteristics of an areaof a patient's body within which the stimulation target is located.Stimulation may include the activation and control of a stimulation gridarray (in which elements of the array can be activated to createdifferent electrode spacing) or a set of spatially discrete stimulatorsthat are configured or operated according to results provided by thesimulation with the goal of increasing the probability that stimulationwill successfully modulate target tissue by improving eTENS. In anembodiment, a grid electrode can allow the electrically active area of amonopolar electrode to functionally be longer or shorter by activatingmore or less electrode contacts on the ventral surface of the gridelectrode. This may provide an advantage since FIGS. 29A-C show thatincreasing the length of the TENS electrode can increase the relativeexcitation of the target nerve. The adjustment of length can also beused to increase patient comfort (e.g. longer length of activemonopole), unless this results in unwanted muscle activation or otherside effects. Additionally, rather than using entire rows during anactivation, the array stimulator can activate the electrode contactelements 1-4 of row 1, elements 5-8 of row 4, and elements 9-12 of row8. Rather than horizontal rows, the grid stimulator can also activateother patterns such as a diagonal row in order to provide stimulationarrays that are oriented correctly with respect to the edges of the IPC.The grid array can provide arbitrary activation patterns rather and gridelement shapes.

The modules described for the apparatus 50 are for illustration purposesonly and the subject invention can have less than or more than themodules and system components described in this specification, or can berealized in alternative embodiments. For example, rather than having aprotocols and parameters module 66, the information related tostimulation protocols and parameters can be simply stored in the memorymodule 60. Disclosed components and modules may be omitted and modulesmay communicate with, and share, resources of other modules. Any of thesystem components or modules can be realized partially or fully in thephysician/patient programmer 70, remote computer 70′, orneurostimulation system 50. The modules may reside within the device 50housing or may exist externally and communicate. The apparatus 50 may berealized as a portable or desktop instrument that controls accessories.The system can be implemented, at least in part, as customized hardwarethat operates with a smart-phone or tablet computer or whichcommunicates with the smartphone or computer so that some disclosedmodules are realized by the smart phone or computer.

The subject systems and methods may be realized using variousinstruments and stimulators distributed by companies such as Uroplasty,Electrocore, Medtronic, StimGuard, Halo Neuroscience (e.g., tDCS, tACS),and eNEURA (e.g., TMS), for providing various types of stimulation. Thisincludes electrical, magnetic, microwave or other stimulation directedeither to implantable components that stimulate tissue or to the tissueitself. Stimulation provided by at least one of TENS, eTENS,percutaneous, external, partially or fully implantable systems can beoperated to provide stimulation using the protocols and nerve targetsdisclosed herein. Patients (including children with urinary disorders)may be treated with either TENS, percutaneous, or implanted devices as ameans of reducing their OAB symptoms that include incontinence andnocturia, or treating various pelvic floor disorders by SAFNstimulation.

The term OAB is used herein can be generally be understood to includedisorders such as incontinence, bladder pain, fecal incontinence, andpelvic floor disorders and their symptoms. Treatment can include relieffrom symptoms, improvement of abnormal activity, etc.

The foregoing description of preferred embodiments for this disclosurehave been presented for purposes of illustration and description. Theyare not intended to limit the invention to the precise forms disclosed.Obvious modifications or variations are possible in light of the aboveteachings. The different embodiments are chosen and described in aneffort to provide the best illustrations of the principles of theinvention and its practical application, and to thereby enable one ofordinary skill in the art to utilize the invention in variousembodiments and with various modifications as are suited to theparticular use contemplated. All these modifications and variations arewithin the scope of the invention as determined by the appended claimswhen interpreted in accordance with the breadth to which they areentitled.

We claim:
 1. A method of treating an overactive bladder of a patientincluding the steps of: establishing at least two transcutaneouselectrical neural stimulation (TENS) electrodes; establishing aneurostimulator configurable to provide a treatment stimulation signalto the TENS electrodes according to a stimulation protocol that isdefined for stimulation of the saphenous nerve for the treatment of thepatient's overactive bladder; positioning at least one of the two TENSelectrodes on the inner side of the patient's leg in the area near theupper calf; actuating said neurostimulator to provide a test stimulationsignal and assessment in order to determine if at least one of atingling, vibrating, buzzing, pressure, electrotactile tactilesensation, warmth, or tickling sensation is experienced which radiatesaway from the location of at least one of the two electrodes; whereby(1) when application of the test stimulation signal fails to produce aradiating sensation indicating that the saphenous nerve has beenstimulated, then performing the step of either increasing the teststimulation signal or adjusting the position of at least one of the twoTENS electrodes and (2) when the test stimulation signal produces theradiating sensation, then providing stimulation treatment using astimulation signal strength which is not painful to the patient.
 2. Themethod of claim 1, wherein the step of determining if a sensation occursincludes the step of determining if the sensation is radiating away froman electrode and down the leg towards or into the foot.
 3. The method ofclaim 1, further including the steps of providing instructions to placea second lower electrode so that it is vertically displayed from thefirst electrode and near the medial malleolus or the sole of the footand determining if a sensation occurs which is at least one of:radiating away from the first electrode and down the leg, or away fromthe second lower electrode and up the leg.
 4. The method of claim 1,including providing user instructions related to actuating saidneurostimulator to provide a test stimulation signal and performassessment wherein said user instructions include at least one of: a.written instructions; b. illustrations of the leg with graphicdepictions of the location on the medial surface of the leg where theTENS electrodes should be placed; c. illustrations of the leg withgraphic depictions of the location on the medial surface of the legwhere a TENS array should be placed; d. instructions provided by amobile device app or a mobile device; e. an audio-message ofinstructions; f verbal instructions; g. instructions to use a devicesuch as an ultrasound, infrared, or electrical impedance device in orderto located the saphenous nerve or saphenous vein; h. instructionsprovided in combination with either a virtual reality or holographicdisplay; i. instructions provided by a mixed media technology such as aDVD, and, j. a website address where user instructions are provided. 5.The method of claim 1, wherein said at least two TENS electrodes arerealized as part of an accessory such as an electrode array thatpositions the electrodes on the medial aspect of a patient's leg.
 6. Themethod of claim 1, wherein said at least two TENS electrodes arerealized within an electrode array that is connected to at least oneband that is configured to be wrapped around the calf of a patient andto position the array vertically along the inner side of the leg and theat least first electrode is above the at least second electrode.
 7. Themethod of claim 1, further including at least one wearable band that isconfigured to be attached to at least one electrode and to wrap aroundthe area of a patient's (1) upper calf, (2) mid-calf, or (3) entire legto secure and bias the one electrode to the area between the upper calfmuscle and the tibia.
 8. The method of claim 1, further including anexternal patient programmer which is configured to communicate with andprovide user control of the neurostimulator wherein at least one of theneurostimulator and external patient programmer are configured tomonitor usage and assess compliance with respect to a treatment programthat is related to treatment of overactive bladder.
 9. The method ofclaim 1, further including establishing an external patient programmerwhich is configured to obtain user input and to communicate with andprovide user control of the neurostimulator wherein at least one of theneurostimulator and external patient programmer are configured toprovide patient alert reminders related to a stimulation program that isdefined for the treatment of overactive bladder.
 10. The method of claim1, further including providing an external patient programmer which isconfigured to obtain user input and to communicate with and provide usercontrol of the neurostimulator wherein at least one of theneurostimulator and external patient programmer are configured to queryabout bladder activity, bladder pressure, urinary leakage and/or urgencyepisodes measured by wearable or implantable sensors.
 11. The method ofclaim 1, further including establishing an external patient programmerwhich is configured to obtain user input and to communicate with andprovide user control of the neurostimulator wherein at least one of theneurostimulator and external patient programmer are configured to querythe patient about a symptom characteristic such as severity or frequencyrelated to overactive bladder symptoms and to store the response. 12.The method of claim 1, further including establishing an externalpatient programmer which is configured to obtain user input and tocommunicate with and provide user control of the neurostimulator whereinat least one of the neurostimulator and external patient programmer areconfigured to allow the patient to input information related to abladder diary, including if a void event was associated with urgency orleakage.
 13. The method of claim 1, further including providing anexternal patient programmer which is configured to obtain user input andto communicate with and provide user control of the neurostimulatorwherein at least one of the neurostimulator and external patientprogrammer are configured to query the patient to input informationabout at least one of: whether any voiding events occurred during night,whether voiding events awoke the patient, whether voiding events wereaccompanied by urgency or leakage.
 14. The method of claim 1, furtherincluding providing instructions related to setting a stimulationprotocol that is defined for stimulation of the saphenous nerve for thetreatment of the patient's overactive bladder which includes setting thestimulation signal to be at least one of: a signal between 5 and 20 Hz,a 10 Hz signal, a 20 Hz signal, and a signal that roves between 10 and20 Hz.
 15. The method of claim 1, wherein the stimulation signal isdefined to be at least one of: skin threshold (Tskin), maximum tolerance(Tmax), and a signal that roves between Tskin and Tmax, by continuouslyor periodically adjusting amplitude, stimulus pulse width, and/or periodin the case of a sinusoidal waveform.
 16. The method of claim 1, whereinthe external patient programmer is further configured to graphicallydisplay data related to overactive-bladder-related symptoms as summarystatistics or trend charts.
 17. The method of claim 1, wherein theexternal device or programmer determines the therapeutic protocol for agiven week or longer periods based upon at least one of: time since thestart of therapy, number of stimulation sessions provided since thestart of therapy, rate of stimulation sessions provided since the startof therapy, and improvements, worsening, or no change in symptoms ascalculated upon patient input data.
 18. The method of claim 1, whereinthe neurostimulator is further provided with an accelerometer and isconfigured to analyze the accelerometer data including activity data andorientation data, in order to determine using at least one of activitydata and orientation data if a user is likely doing at least oneactivity of: walking, getting out of bed, or moving with a gait that isover a selected rate, and if so then making a modification of theoperation of the stimulus generator which may include pausing ordecreasing the provision of stimulation until analysis of theaccelerometer data determines that the user has stopped the activity.19. An apparatus for transcutaneous electrical nerve stimulation inhumans, the apparatus comprising: a housing; stimulation generatormounted within the housing for electrically stimulating nerves; anelectrode array releasably mounted to the housing and connectable to thestimulation generator, the electrode array comprising a plurality of atleast two electrodes for electrical stimulation of nerves; at least oneuser control mounted to the housing and electrically connected to a userinterface module to control the stimulation generator for controlling atleast one characteristic of a stimulation signal generated by thestimulus generator; monitoring circuitry mounted to the housing andelectrically connected to the stimulation means for monitoring impedancein order to assess electrode contact with patient skin; user interfacemodule mounted within the housing and electrically connected to thecontrol means for controlling the stimulus generator; display meansmounted to the housing and electrically connected to the control userinterface module and the monitoring circuitry for displaying the statusinformation related to the device; and at least one strap attached to atleast one of the housing and the electrode array; wherein the strap isconfigured to hold at least one of the housing and the electrode arrayso that the array stimulates a specific anatomical location to treatoveractive bladder by stimulation of the saphenous nerve using at leasttwo vertically displayed electrodes.
 20. An apparatus according to claim19 wherein said anatomical location is the medial surface of the uppercalf area between the calf muscle and the tibia of a patient.